Piperazine derivatives as tachykinin antagonists

ABSTRACT

This invention relates to piperazine derivatives of the formula:  
                 
 
     wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or Tachykinin-mediated diseases in human being or animals.

TECHNICAL FIELD

[0001] The present invention relates to new piperazine derivatives and apharmaceutically acceptable salt thereof.

[0002] More particularly, it relates to new piperazine derivatives and apharmaceutically acceptable salt thereof which have pharmacologicalactivities such as Tachykinin antagonism, especially Substance Pantagonism, Neurokinin A antagonism, Neurokinin B antagonism, and thelike, to a process for preparation thereof, to a pharmaceuticalcomposition comprising the same, and to a use of the same as amedicament.

[0003] Accordingly, one object of the present invention is to providenew and useful piperazine derivatives and a pharmaceutically acceptablesalt thereof which have pharmacological activities such as Tachykininantagonism, especially Substance P antagonism, Neurokinin A antagonism,Neurokinin B antagonism, and the like.

[0004] Another object of the present invention is to provide a processfor the preparation of said piperazine derivatives and a salt thereof.

[0005] A further object of the present invention is to provide apharmaceutical composition comprising, as an active ingredient, saidpiperazine derivatives and a pharmaceutically acceptable salt thereof.

[0006] Still further object of the present invention is to provide a useof said piperazine derivatives or a pharmaceutically acceptable saltthereof as Tachykinin antagonist, especially Substance P antagonist,Neurokinin A antagonist or Neurokinin B antagonist, useful for treatingor preventing Tachykinin-mediated diseases, for example, respiratorydiseases such as asthma, bronchitis, rhinitis, cough, expectoration, andthe like; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; cutaneous diseases such as contactdermatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis, and the like; inflammatory diseases such as rheumatoidarthritis, osteoarthritis, and the like; pains or aches (e.g., migraine,headache, toothache, cancerous pain, back pain, etc.); and the like inhuman being or animals.

BACKGROUND ART

[0007] Some piperazine derivatives having pharmaceutical activities suchas Tachykinin antagonism have been known as described in EP 0655442 A1.

DISCLOSURE OF INVENTION

[0008] The object compound of the present invention can be representedby the following general formula (I):

[0009] wherein

[0010] Y is bond or lower alkylene,

[0011] R¹ is aryl which may have suitable substituent(s),

[0012] R² is aryl or indolyl each of which may have suitablesubstituent(s),

[0013] R³ is hydrogen or lower alkyl,

[0014] R⁴ is chloro(lower)alkenyl;

[0015] chloro(lower)alkynyl;

[0016] pyridyl(lower)alkylamino(lower)alkyl;

[0017] pyridyl(lower)alkylamino(lower)alkenyl;

[0018] N-,(lower alkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl;

[0019] triazolylamino(lower)alkyl;

[0020] lower alkoxy(lower)alkylamino(lower)alkyl;

[0021] bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;

[0022] N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;

[0023] hydroxy(lower)alkyl;

[0024] lower alkylsulfonyloxy(lower)alkyl;

[0025] phenyl(lower)alkyl which may have lower alkanoyl, amino, loweralkanoylamino, di(lower)alkylaminocarbonyl or nitro;

[0026] lower alkoxyphenyl(lower)alkylcarbonyl;

[0027] lower alkanoylbenzoyl;

[0028] benzoyl(lower)alkyl which has lower alkyl, chlorine ordi(lower)alkylamino;

[0029] benzoyl(lower)alkyl which has halogen and lower alkyl;

[0030] dihalobenzoyl(lower)alkyl;

[0031] di(lower)alkylbenzoyl(lower)alkyl;

[0032] 3-fluorobenzoyl(lower)alkyl;

[0033] 3- (4-fluorobenzoyl)propyl;

[0034] 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;

[0035] piperazinylcarbonyl(lower)alkyl which has cyclopentyl orhalophenyl;

[0036] (2-pyridyl)(lower)alkyl;

[0037] (3-pyridyl)propyl;

[0038] (3-pyridyl)(lower)alkynyl;

[0039] imidazolyl(lower)alkyl which may have lower alkyl;

[0040] pyrazolyl(lower)alkyl which may have lower alkyl;

[0041] thiomorpholinylcarbonyl(lower)alkyl;

[0042] (3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; orthienylcarbonyl(lower)alkyl,

[0043] 1,2,3,6-tetrahydropyridyl(lower)alkyl,

[0044] 1,2,3,6-tetrahydropyridyl(lower)alkynyl,

[0045] 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,

[0046] 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl,

[0047] saturated heterocyclic(lower)alkyl,

[0048] saturated heterocyclic(lower)alkenyl,

[0049] saturated heterocyclic(lower)alkynyl,

[0050] saturated heterocyclicamino(lower)alkyl,

[0051] saturated heterocyclicamino(lower)alkenyl or

[0052] saturated heterocyclicamino(lower)alkynyl, each of which may havesuitable substituent(s),

[0053] and a pharmaceutically acceptable salt thereof.

[0054] It is to be noted that the object compound (I) may include one ormore stereoisomers due to asymmetric carbon atom(s) and double bond, andall of such isomers and a mixture thereof are included within the scopeof the present invention.

[0055] It is further to be noted that isomerization or rearrangement ofthe object compound (I) may occur due to the effect of the light, acid,base or the like, and the compound obtained as the result of saidisomerization or rearrangement is also included within the scope of thepresent invention.

[0056] It is also to be noted that the solvating form of the compound(I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I)are included within the scope of the present invention.

[0057] According to the present invention, the object compound (I) or asalt thereof can be prepared by processes which are illustrated in thefollowing schemes.

Process 1

[0058]

Process 2

[0059]

Process 3

[0060]

Process 4

[0061]

Process 5

[0062]

Process 6

[0063]

Process 7

[0064]

[0065] wherein

[0066] Y, R¹, R₂, R³ and R⁴ are each as defined above,

[0067] X is lower alkylene,

[0068] R⁵ is lower alkoxyphenyl(lower)alkyl or lower alkanoylphenyl,

[0069] R⁶ is piperazinyl which has cyclopentyl or halophenyl; orthiomorpholinyl,

[0070] R⁷ is acyloxy,

[0071] R⁸ is pyridyl(lower)alkylamino;

[0072] N-(lower alkyl)-N-[pyridyl(lower)alkyl]amino;

[0073] triazolylamino; morpholinoamino;

[0074] lower alkoxy(lower)alkylamino;

[0075] bis[(lower)alkoxy(lower)alkyl]amino;

[0076] N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino;

[0077] imidazolyl; pyrazolyl; or 1,2,3,6-tetrahydropyridyl,

[0078] 1,2,3,4-tetrahydroisoquinolyl,

[0079] 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturatedheterocyclic, each of which may have suitable substituent(s),

[0080] R⁹ is lower alkanoyl, and

[0081] W₁ and W₂ are each a leaving group.

[0082] As to the starting compounds (II), (III), (IV), (V), (VI), (VII)and (VIII), some of them are novel and can be prepared by the proceduresdescribed in the Preparations and Examples mentioned later or similarmanners thereto.

[0083] Suitable salts and pharmaceutically acceptable salts of thestarting and object compounds are conventional non-toxic salt andinclude an acid addition salt such as an organic acid salt (e.g.acetate, trifluoroacetate, fumarate, maleate, tartrate,methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), aninorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide,sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g.arginine, aspartic acid, glutamic acid, etc.), or a metal salt such asan alkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.)andan ammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N′-dibenzylethylenediamine salt, etc.), or the like.

[0084] In the above and subsequent descriptions of the presentspecification, suitable examples and illustrations of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows.

[0085] The term “lower” is intended to mean 1 to 6, preferably 1 to 4,carbon atom(s), unless otherwise indicated.

[0086] Suitable “lower alkylene” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene,propylene, tetramethylene, methylmethylene, methyltrimethylene,hexamethylene, and the like, in which the preferred one is methylene,ethylene, trimethylene or methylmethylene.

[0087] Suitable “halogen” and “halogen moiety” in the term“dihalobenzoyl(lower)alkyl” and “halophenyl” may include fluorine,chlorine, bromine and iodine.

[0088] Suitable “lower alkyl” and “lower alkyl moiety” in the terms“pyridyl(lower)alkylamino(lower)alkyl”,“pyridyl(lower)alkylamino(lower)alkenyl”, “N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl”,“triazolylamino(lower)alkyl”, “lower alkoxy(lower)alkylamino(lower)alkyl”, “bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl”,“N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl”,“hydroxy(lower)alkyl”, “lower alkylsulfonyloxy(lower)alkyl”,“phenyl(lower)alkyl”, “di(lower)alkylaminocarbonyl”, “loweralkoxyphenyl(lower)alkylcarbnonyl”, “benzoyl(lower)alkyl”,“di(lower)alkylamino”, “benzoyl(lower)alkyl”,“dihalobenzoyl(lower)alkyl”, “di(lower)alkylbenzoyl(lower)alkyl”,“3-fluorobenzoyl(lower)alkyl”, “piperazinylcarbonyl(lower)alkyl”,“(2-pyridyl)(lower)alkyl”, “imidazolyl(lower)alkyl”,“pyrazolyl(lower)alkyl”, “thiomorpholinylcarbonyl(lower)alkyl”,“(3-azabicyclo[3.2.2non-3-yl)carbonyl(lower)alkyl”,“thienylcarbonyl(lower)alkyl”, “1,2,3,6-tetrahydropyridyl(lower)alkyl”,“1,2,3,4-tetrahydroisoquinolyl(lower)alkyl”,“4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl”, “saturatedheterocyclic(lower)alkyl”, “saturated heterocyclicamino(lower)alkyl” and“lower alkoxyphenyl(lower)alkyl” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl and the like, preferably one having 1 to5 carbon atom(s).

[0089] Suitable “lower alkenyl moiety” in the terms“chloro(lower)alkenyl”, “pyridyl(lower)alkylamino(lower)alkenyl”,“saturated heterocyclic(lower)alkenyl” and “saturatedhreterocyclicamino(lower)alkenyl” may include vinyl, 1-(or 2-)propenyl,1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or2-)propenyl, 1- (or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferableexample may be C₂-C₄ alkenyl.

[0090] Suitable “lower alkynyl moiety” in the terms“chloro(lower)alkynyl”, “(3-pyridyl)(lower)akynyl”,“1,2,3,6-tetrahydropyridyl(lower)alkynyl”, “saturatedheterocyclic(lower)alkynyl” and “saturatedheterocyclicamino(lower)alkynyl” may include ethynyl, 1-propynyl,propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl and the like, in which morepreferable example may be C₂-C₅ alkynyl.

[0091] Suitable “aryl” may include phenyl, naphthyl, and the like, inwhich the preferred one is C₆-C₁₀ aryl and the most preferred one isphenyl.

[0092] Suitable “lower alkanoyl” and “lower alkanoyl moiety” in theterms “lower alkanoylamino”, “lower alkanoylbenzoyl” and “loweralkanoylphenyl” may include formyl, acetyl, propanoyl, butanoyl,2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and thelike.

[0093] Suitable “lower alkoxy moiety” in the terms “loweralkoxyphenyl(lower)alkylcarbonyl” and “lower alkoxyphenyl(lower)alkyl”may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.

[0094] Suitable “saturated heterocylic” and “saturated heterocyclicmoiety” in the terms “saturated heterocyclic(lower) alkyl”, “saturatedheterocyclic(lower)alkynyl”, “saturated heterocyclicamino(lower)alkyl”,“saturated heterocyclicamino(lower)alkenyl” and “saturatedheterocyclicamino(lower)alkynyl” may include

[0095] saturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,hexamethyleneimino, etc;

[0096] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

[0097] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.;

[0098] saturated heterobicyclic group of the formula:

[0099] saturated heterobicyclic group of the formula:

[0100] Suitable “substituent” in the terms “aryl which may have suitablesubstituent(s)”, “aryl or indolyl each of which may have suitablesubstituent(s)”, “thienylcarbonyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkynyl,1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl, saturatedheterocyclic(lower)alkyl, saturated heterocyclic(lower) alkenyl,saturated heterocyclic(lower)alkynyl, saturatedheterocyclicamino(lower)alkyl, saturated heterocyclicamino(lower)alkenylor saturated heterocyclicamino(lower)alkynyl, each of which may havesuitable substituent(s)” and 1,2,3,4-tetrahydroisoquinolyl,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic eachof which may have suitable substituent(s)” may include lower alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, neopentyl, tert-pentyl, hexyl, etc.), cyclo(lower)alkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy,pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.), loweralkoxy(lower)alkyl (e.g., methoxymethyl, ethoxymethyl, 1-methoxyethyl,2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl(e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), loweralkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl,etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl,1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl(e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.), halogen(e.g., chlorine, bromine, fluorine and iodine), carboxy, protectedcarboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl,etc.), ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl,phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl wherein lower alkylmoiety can be referred to the ones as exemplified above, protectedcarboxy(lower)alkyl wherein lower alkyl moiety can be referred to theones as exemplified above, nitro, amino, protected amino,di(lower)alkylamino (e.g., dimethylamino, diethylamino,diisopropylamino, ethylmethylamino, isopropylmethylamino,ethylisopropylamino, etc.), hydroxy(lower)alkyl, protectedhydroxy(lower)alkyl, acyl, cyano, oxo, mercapto, lower alkylthio (e.g.,methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.),lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.), imino,morpholinyl (e.g., 2-morpholinyl, 3-morpholinyl, morpholino), bivalentgroup of the formula:

[0101] and the like.

[0102] Suitable “leaving group” may include lower alkoxy (e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy,etc.), aryloxy (e.g. phenoxy, naphthoxy, etc.), an acid residue or thelike.

[0103] Suitable “acid residue” may be halogen (e.g. chlorine, bromine,iodine, etc.), sulfonyloxy (e.g. methylsulfonyloxy, phenylsulfonyloxy,mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.

[0104] Suitable “acyloxy” may include hydroxysulfonyloxy, loweralkylsulfonyloxy (e.g. methylsulfonyloxy, ethylsulfonyloxy, etc.),phosphonooxy, and the like.

[0105] Preferred embodiments of the object compound (I) are as follows:

[0106] Y is lower alkylene (more preferably C₁-C₄ alkylene, mostpreferably methylene);

[0107] R¹ is aryl (more preferably C₆-C₁₀ aryl, most preferably phenyl)which may have 1 to 3 (more preferably 1 or 2; most preferably 2)suitable substituent(s) [more preferably mono (or di ortri)halo(lower)alkyl (more preferably trihalo(lower)alkyl, mostpreferably trifluoromethyl)];

[0108] R² is aryl (more preferably C₆-C₁₀ aryl, most preferably phenylor naphthyl) or indolyl each of which may have 1 to 3 (more preferably 1or 2, most preferably 2) suitable substituent(s) [more preferablysubstituent selected from the group consisting of lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl), lower alkoxy (morepreferably C₁-C₄ alkoxy, most preferably methoxy), mono(or di ortri)halo(lower)alkyl (more preferably mono(or di ortri)halo(C₁-C₄)alkyl, most preferably trifluoromethyl) and halogen (morepreferably chlorine or fluorine)];

[0109] R³ is hydrogen; and

[0110] R⁴ is chloro(lower)alkenyl (more preferably chloro(C₂-C₄)alkenyl,most preferably 4-chloro-2-butenyl); chloro(lower)alkynyl (morepreferably chloro(C₂-C₄)alkynyl, most preferably 4-chloro-2-butynyl);pyridyl(lower)alkylamino(lower)alkyl [more preferablypyridyl(C₁-C₄)alkylamino(C₁-C₄)alkyl, most preferably2-[(3-pyridylmethyl)amino]ethyl, 2-[(4-pyridylmethyl)amino]ethyl or3-[(3-pyridylmethyl)amino]propyl];pyridyl(lower)alkylamino(lower)alkenyl (more preferablypyridyl(C₁-C₄)alkylamino(C₂-C₄)alkenyl, most preferably4-[(3-pyridylmethyl)amino]-2-butenyl); N-loweralkyl)-N-[pyridyl(lower)alkyl]amino(lower)alkyl (more preferablyN-(C₁-C₄ alkyl)-N-[pyridyl(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, morepreferably 2-[N-methyl-N-(3-pyridylmethyl) amino]ethyl];triazolylamino(lower)alkyl (more preferably triazolylamino(C₁-C₄)alkyl,most preferably 3-(1,2,4-triazol-3-ylamino) propyl); loweralkoxy(lower)alkylamino(lower)alkyl (more preferably C₁-C₄alkoxy(C₁-C₄)alkylamino(C₁-C₄)alkyl, most preferably2-(2-methoxyethyl)aminoethyl);bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl [more preferablybis[(C₁-C₄)alkoxy(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, most preferably3-[bis(2-methoxyethyl)amino]propyl]; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl [more preferablyN-(C₁-C₄ alkyl)-N-[(C₁-C₄)alkoxy(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, mostpreferably 2-[N-methyl-N-(2-methoxyethyl)amino]ethyl];hydroxy(lower)alkyl (more preferably hydroxy (C₁-C₄)alkyl, mostpreferably hydroxypropyl); lower alkylsulfonyloxy(lower)alkyl (morepreferably C₁-C₄ alkylsulfonyloxy(C₁-C₄)alkyl, most preferablymethylsulfonyloxyropyl); phenyl(lower)alkyl (more preferablyphenyl(C₁-C₄)alkyl, most preferably benzyl) which may have loweralkanoyl (more preferably C₁-C₄ alkanoyl, most preferably acetyl, amino,lower alkanoylamino (more preferably C₁-C₄ alkanoylamino, mostpreferably acetylamino), di(lower)alkylaminocarbonyl (more preferablydi(C₁-C₄)alkylaminocarbonyl, most preferably diethylaminocarbonyl) ornitro; lower alkoxyphenyl(lower)alkylcarbonyl (more preferably C₁-C₄alkoxyphenyl (C₁-C₄) alkylcarbonyl, most preferablymethoxyphenylmethylcarbonyl); lower alkanoylbenzoyl (more preferablyC₁-C₄ alkanoylbenzoyl, most preferably acetylbenzoyl);benzoyl(lower)alkyl (more preferably benzoyl(C₁-C₄)alkyl, mostpreferably benzoylmethyl) which has lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl), chlorine or di(lower)alkylamino (morepreferably di(C₁-C₄) alkylamino, most preferably dimethylamino);benzoyl(lower)alkyl (more preferably benzoyl(C₁-C₄)alkyl, mostpreferably benzoylmethyl) which has halogen (more preferably fluorine)and lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl);dihalobenzoyl(lower)alkyl [more preferably dihalobenzoyl(C₁-C₄)alkyl,most preferably (difluorobenzoyl)methyl];di(lower)alkylbenzoyl(lower)alkyl [more preferablydi(C₁-C₄)alkylbenzoyl(C₁-C₄)alkyl, most preferablydimethylbenzoylmethyl]; 3- fluorobenzoyl(lower)alkyl, more preferably3-fluorobenzoyl (C₁-C₄)alkyl, most preferably 3-fluorobenzoylmethyl);3-(4-fluorobenzoyl)propyl; 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;piperazinylcarbonyl(lower)alkyl (more preferablypiperazinylcarbonyl(C₁-C₄)alkyl, most preferablypiperazinylcarbonylmethyl) which has cyclopentyl or halophenyl (morepreferably fluorophenyl); (2-pyridyl)(lower)alkyl (more preferably(2-pyridyl)(C₁-C₄) alkyl, most preferably (2-pyridyl)methyl);(3-pyridyl)propyl (more preferably 3-(3-pyridyl)propyl);(3-pyridyl)(lower)alkynyl (more preferably (3-pyridyl) (C₂-C₄)alkynyl,most preferably 3-(3-pyridyl)-2-propynyl); imidazolyl(lower) alkyl (morepreferably imidazolyl (C₁-C₄)alkyl, most preferably(1-imidazol-1-yl)methyl, (1H-imidazol-2-yl)methyl or(1H-imidazol-4-yl)methyl) which may have lower alkyl (more preferablyC₁-C₄ alkyl, most preferably methyl); pyrazolyl(lower)alkyl (morepreferably pyrazolyl (C₁-C₄)alkyl, most preferably(1H-pyrazol-4-yl)methyl or 3- (1H-pyrazol-4-yl) propyl) which may havelower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl);thiomorpholinylcarbonyl(lower)alkyl (more preferablythiomorpholinylcarbonyl (C₁-C₄)alkyl, most preferablythiomorpholinylcarbonylmethyl);(3-azabicyclor[3.2.2non-3-yl)carbonyl(lower)alkyl (more preferably(3-azabicyclo[3.2.2]non-3-yl)carbonyl(C₁-C₄)alkyl, most preferably(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl); orthienylcarbonyl(lower)alkyl (more preferablythienylcarbonyl(C₁-C₄)alkyl, most preferably thienylcarbonylmethyl),1,2,3,6-tetrahydropyridyl(lower)alkyl (more preferably1,2,3,6-tetrahydropyridyl(C₁-C₄)alkyl, most preferably3-(1,2,3,6-tetrahydropyridin-1-yl) propyl),1,2,3,6-tetrahydropyridyl(lower)alkynyl (more preferably1,2,3,6-tetrahydropyridyl(C₂-C₄)alkynyl, most preferably4-(1,2,3,6-tetrahydropyridin-1-yl)-2-bultynyl),1,2,3,4-tetrahydroisoquinolyl(lower)alkyl (more preferably1,2,3,4-tetrahydroisoquinolyl(C₁-C₄) alkyl, most preferably1,2,3,4-tetrahydroisoquinolylpropyl),4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl (more preferably4,5,6,7-tetrahydrothieno[3,2-c7-pyridinyl (C₁-C₄)alkyl, most preferably4,5,6,7-tetrahydrothieno[3,2-c]pyridinylpropyl), saturatedheterocyclic(lower)alkyl (more preferably saturatedheterocyclic(C₁-C₄)alkyl, more preferably saturated heterocyclicethyl orsaturated heterocyclicpropyl, most preferably saturatedheterocyclicpropyl), saturated heterocyclic(lower)alkenyl (morepreferably saturated heterocyclic(C₂-C₄)alkenyl, most preferablysaturated heterocyclicbutenyl), saturated heterocyclic(lower)alkynyl(more preferably saturated heterocyclic(C₂-C₅)alkynyl, most preferablysaturated heterocyclicbutynyl or saturated heterocyclicpentynyl),saturated heterocyclicamino(lower)alkyl (more preferably saturatedheterocyclicamino(C₁-C₄)alkyl, most preferably saturatedheterocyclicaminopropyl), saturated heterocyclicamino(lower)alkenyl(more preferably saturated heterocyclicamino(C₂-C₄)alkenyl, mostpreferably saturated heterocyclicaminobutenyl) or saturatedheterocyclicamino(lower)alkynyl (more preferably saturatedheterocyclicamino(C₂-C₅)alkynyl, most preferably saturatedheterocyclicaminobutynyl) wherein “saturated heterocyclic moiety” issaturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 (more preferably 1 or 2)nitrogen atom(s) (more preferably pyrrolidinyl, piperidyl, piperazinylor hexamethyleneimino, most preferably piperidyl); saturated 3 to8-membered (more preferably 5 to 7-membered) heteromonocyclic groupcontaining 1 or 2 (more preferably 1) oxygen atom(s) and 1 to 3 (morepreferably 1) nitrogen atom(s) (more preferably morpholinyl orhomomorpholinyl, most preferably morpholinyl); saturated 3 to 8-membered(more preferably 5 or 6-membered) heteromonocyclic group containing 1 or2 (more preferably 1) sulfur atom(s) and 1 to 3 (more preferably 1)nitrogen atom(s) (more preferably thiomorpholinyl); or saturatedheterocyclic group of the formula:

[0111]  (more preferably 3-azabicyclo[3.2.2]non-3-yl)], each of whichmay have 1 to 3 (more preferably 1 or 2) suitable substituent(s) [morepreferably substituent selected from the group consisting ofcyclo(lower)alkyl (more preferably cyclohexyl), lower alkanoyl (morepreferably C₁-C₄ alkanoyl, most preferably acetyl), lower alkyl (morepreferably C₁-C₄ alkyl, most preferably methyl), mono(or di ortri)halo(lower)alkyl (more preferably monohalo(C₁-C₄)alkyl, mostpreferably fluoromethyl), lower alkoxy (more preferably C₁-C₄ alkoxy,most preferably methoxy), lower alkoxy(lower)alkyl (more preferablyC₁-C₄ alkoxy(C₁-C₄)alkyl, most preferably methoxymethyl), halogen (morepreferably chlorine), aryl (more preferably phenyl), cyano, oxo andbivalent group of the formula:

[0112] More preferred embodiments of the object compound (I) are asfollows:

[0113] Y is lower alkylene (more preferably C₁-C₄ alkylene, mostpreferably methylene);

[0114] R¹ is phenyl which may have 1or 2 mono(or di or tri)halo(lower)alkyl [more preferably bis(trihalo(lower)alkyl)phenyl, most preferablybis(trifluoromethyl)phenyl];

[0115] R² is phenyl which may have 1 or 2 suitable substituent(s)selected from the group consisting of lower alkyl, lower alkoxy, mono(ordi or tri)halo(lower)alkyl and halogen [more preferablydi(lower)alkylphenyl, (lower)alkoxyphenyl, [trihalo(lower)alkylphenyl,[(lower)alkylhalophenyl, halophenyl or dihalophenyl, most preferablydimethylphenyl, methoxyphenyl, (trifluoromethyl)phenyl,methylfluorophenyl, fluorophenyl or difluorochlorophenyl], naphthyl orindolyl;

[0116] R³ is hydrogen; and

[0117] R⁴ is morpholinyl(lower)alkyl which may have 1 or 2 lower alkyl(more preferably methyl), homomorpholinyl(lower)alkyl,thiomorpholinyl(lower)alkyl, (hexamethyleneimino)(lower)alkyl,(3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl, piperazinyl(lower)alkyl whichmay have phenyl or cyclo(lower)alkyl (more preferablypiperazinyl(lower)alkyl which has phenyl or cyclohexyl),morpholinyl(lower)alkenyl which may have 1 or 2 lower alkyl (morepreferably methyl), morpholinyl(lower)alkynyl which may have asubstituent selected from the group consisting of lower alkyl (morepreferably methyl), lower alkoxy(lower)alkyl (more preferablymethoxymethyl) and mono(or di or tri)halo(lower)alkyl (more preferablyfluoromethyl), thiomorpholinyl(lower)alkenyl,thiomorpholinyl(lower)alkynyl, pyrrolidinyl(lower)alkynyl which may havelower alkoxy(lower)alkyl (more preferably methoxymethyl),piperazinyl(lower)alkynyl which may have cyclo(lower)alkyl (morepreferably cyclohexyl), morpholinylamino(lower)alkyl,morpholinylamino(lower)alkenyl, morpholinylamino(lower)alkynyl, orpiperidyl(lower)alkyl which may have 1 or 2 suitable substituent(s)selected from the group consisting of bivalent group of the formula:

[0118] phenyl, cyano, lower alkanoyl, lower alkoxy, piperidinyl, and oxo[more preferably [spiro[indan-1,4′-piperidine]-1′-yl](lower)alkyl,piperidyl(lower)alkyl which has phenyl, acetyl, methoxy, piperidino oroxo, or piperidyl(lower)alkyl which has phenyl and cyano].

[0119] The Processes 1 to 7 for preparing the object compound (I) of thepresent invention are explained in detail in the following.

[0120] Process 1

[0121] The object compound (I) or a salt thereof can be prepared byreacting the compound (II) or its reactive derivative at the imino groupor a salt thereof with the compound (IV) or a salt thereof.

[0122] Suitable reactive derivative at the imino group of the compound(II) may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (II) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (II) with phosphorus trichloride or phosgene and the like.

[0123] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxene,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

[0124] The reaction may also be carried out in the presence of aninorganric or organic base such as alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

[0125] The reaction temperature is not critical, and the reaction isusually carried out under cooling to heating.

[0126] Process 2

[0127] The object compound (Ia) or a salt thereof can be prepared byreacting the compound (V) or its reactive derivative at the carboxygroup or a salt thereof with the compound (II) or its reactivederivative at the imino group or a salt thereof.

[0128] Suitable reactive derivative at the carboxy group of the compound(V) may include an acid halide, an acid anhydride, an activated amide,an activated ester, and the like. The suitable example of the reactivederivative may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, lower alkanesulfonic acid [e.g. methanesulfonicacid, ethanesulfonic acid, etc.], sulfurous acid, thiosulfuric acid,sulfuric acid, aliphatic carboxylic acid [e.g. acetic acid, propionicacid, butyric acid, isobutyric acid, pivalic acid, valeric acid,isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] oraromaticcarboxylic acid [e.g. benzoic acid, etc.]; a symmetrical andanhydride; an activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl[(CH₃)₂N⁺═CH—] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (V) to be used.

[0129] The reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

[0130] In this reaction, when the compound (V) is used in a free acidform or a salt thereof, the reaction is preferably carried out in thepresence of a conventional condensing agent such asN,N′-dichlorohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide; N,N′-diisopropylcarbodiimide; N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thienyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate,isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;2-chloro-1-methylpyridinium, iodide;1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-calledvilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

[0131] The reaction may also be carried out in the presence of aninorganic or organic base such as alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

[0132] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0133] Process 3

[0134] The object compound (Ib) or a salt thereof can be prepared byreacting the compound (III) or its reactive derivative at the carboxygroup or a salt thereof with the compound (VI) or a salt thereof.

[0135] The reaction mode and reaction conditions of this reaction are tobe referred to those as explained in Process 2.

[0136] Process 4

[0137] The object compound (Id) or a salt thereof can be prepared bysubjecting the ccmpound (Ic) or a salt thereof to an acylation reaction.

[0138] The reaction can be carried out in the manner disclosed inExample 20 mentioned later or similar manners thereto.

[0139] Process 5

[0140] The compound (Ie) or a salt thereof can be prepared by reactingthe compound (Id) or a salt thereof with the compound (VII) or a saltthereof.

[0141] This reaction is usually carried out in a solvent such as water,alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, acetontrile, diethyl ether or any other solventswhich do not adversely affect the reaction, or the mixture thereof.

[0142] The reaction temperature is not critical and the reaction isusually carried out under cooling to heating.

[0143] The reaction may be also carried out in the presence of aninorganic or an organic base such as alkali metal (e.g., sodium,potassium, etc.), alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, etc.), alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc), alkali metal(lower)alkoxide (e.g. sodium methoxide,sodium ethoxide, etc.), pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

[0144] When the base and/or the starting compound are in liquid, theycan be used also as a solvent.

[0145] Process 6

[0146] The object compound (Ig) or a salt thereof can be prepared bysubjecting the compound (If) or a salt thereof to a reduction reaction.

[0147] The reaction can be carried out in the manner disclosed inExample 29 mentioned later or similar manners thereto.

[0148] Process 7

[0149] The object compound (Ih) or a salt thereof can be prepared bysubjecting the compound (Ig) or a salt thereof to acylation reaction.

[0150] The reaction can be carried out in the manner disclosed inExample 3 mentioned later or similar manners thereto.

[0151] The object compound (I) and a pharmaceutically acceptable saltthereof have pharmacological activities such as Tachykinin antagonism,especially Substance P antagonism, Neurokinin A antagonism or NeurokininB antagonism, and therefore are useful for treating or preventingTachykinin-mediated diseases, particularly Substance P-mediateddiseases, for example, respiratory diseases such as asthma, bronchitis(e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis,etc.), rhinitis, couph, expectoration, and the like; opthalmic diseasessuch as conjunctivitis, vernal conjunctivitis, and the like; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis, and the like; inflammatory diseases such asrheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g.migraine, headache, cluster headache, toothache, cancerous pain, backpain, neuralgia, etc.); and the like.

[0152] Further, it is expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing ophthalmic diseases such as glaucoma,uveitis, and the like; gastrointestinal diseases such as ulcer,ulcerative colitis, irritable bowel syndrome, food allergy, and thelike; inflammatory diseases such as nephritis, and the like; circulatorydiseases such as hypertension, angina pectoris, cardiac failure,thrombosis, Raynaud's disease, and the like; epilepsy; spasticparalysis; pollakiuria; cystitis; bladder detrusor hyperreflexia;urinary incontinence; Parkinson diseases; dementia; AIDS relateddementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea;carcinoid syndrome; disorders related to immune enhancement orsuppression; disorders caused by Helicobacter pylori or another spiralurease-positive gram-negative bacterium; sunburn; angiogenesis ordiseases caused by angiogenesis; and the like.

[0153] It is furthermore expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing chronic obstructive pulmonarydiseases, particularly chronic pulmonary emphysema; iritis;proliferative vitreoretinopathy; psoriasis; inflammatory intestinaldiseases, particularly Crohn's diseases; hepatitis; superficial pain oncongelation, burn, herpes zoster or diabetic neuropathy; tenalgiaattended to hyperlipidemia; postoperative neuroma, particularly ofmastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichenplanus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough;pulmonary tuberculosis; cystic fibrosis; emesis; mental diseases,particularly anxiety, depression, dysthymic disorders and schizophrenia;demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis; attenuation of morphine withdrawal; oedema, such asoedema caused by thermal injury; small cell carcinomas, particularlysmall cell lung cancer (SCLC); hypersensitivity disorders such as poisonivy; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; reflex sympathetic dystrophy such asshoulder/hand syndrome; addiction disorders such as alcoholism; stressrelated somatic disorders; rheumatic diseases such as fibrositis; andthe like.

[0154] Furthermore, the object compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention are Central NervousSystem (CNS) penetrant.

[0155] For therapeutic purpose, the compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compound, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral, external including topical, enternal,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal or transocular administration. Thepharmaceutical preparations may be solid, semi-solid or solutions suchas capsules, tablets, pellets, dragees, powders, granules,suppositories, ointments, creams, lotions, inhalants, injections,cataplasms, gels, tapes, eye drops, solution, syrups, aerosols,suspension, emulsion, or the like. If desired, there may be included inthese preparations, auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

[0156] While the dosage of the compound (I) will vary depending upon theage and condition of a patient, an average single dose of about 0.1 mg,1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound(I) may be effective for treating Tachykinin-mediated diseases such asasthma and the like. In general, amounts between 0.1 mg/body and about1,000 mg/body may be administered per day.

[0157] In order to show the utility of the object compound (I) and apharmaceutically acceptable salt thereof, the pharmacological test dataof some representative compounds of the present invention is shown inthe following.

[0158] A. Evaluation of NK₁ Antagonist Transport Efficiency to theCental Nervous System Using a h-NK₁ Receptor Binding Assay

[0159] [I] Test Method

[0160] (1) Administration of Test Compound and Extraction of theCompound From Brain

[0161] Male SD rats were given an i.v. injection of a solutioncontaining a test compound (1 mg/kg). 5 Min later the animals wereanesthetized by ether, bled and perfused through the aorta ascendenswith 20 ml of saline. The brain was rapidly removed, weighed andhomogenized in 4 vol. ice-cold distilled water by using Polytoron(KINEMATICA). To extract the test compound, 500 μl of the homogenate,100 μl of methanol, 500 μl of 0.1 N NaOH and 4 ml of ethyl acetate weremixed by shaking for 10 min at room temperature. The organic phase (2.5ml) was recovered by centrifugation at 3,000 rpm for 10 min, dried anddissolved in dimethyl sulfoxide.

[0162] (2) h-NK₁ Receptor Binding Assay

[0163] (a) Crude CHO Cell Membrane Preparation

[0164] CHO cells permanently expressing h-NK₁ receptors were harvestedand homogenized with a Dounce homogenizer at 4° C. in a buffer (0.25 Msucrose, 25 mM Tris-HCl (pH 7.4), 10 mM MgCl₂, 1 mM EDTA, 5 μg/mlp-APMSF). The homogenate was centrifuged (500×g, 10 min), and the pelletwas resuspended in the same buffer, homogenized, and centrifuged. Thetwo supernatants were combined and centrifuged (100,000×g, 1 hour). Thecrude cell membranes thus isolated were resuspended in a buffer (25 MMTris-HCl (pH 7.4), 10 mM MgCl₂, 1 mM EDTA, 5 μg/ml p-APMSF) and storedat −80° C. until use.

[0165] (b) ¹²⁵I-BH-Substance P Binding to the Prepared Membrane

[0166] Cell membranes (6 μg/ml) were incubated with ¹²⁵I-BH-Substance P(0.1 nM) with or without the extracted compounds in 0.25 ml of a medium(50 mM Tris-HCl (pH 7.4), 5 mM MnCl₂, 20 μg/ml chymrostatin, 40 μg/mlbacitracin, 4 μg/ml leupeptin, 5 μg/ml p-APMSF, 200 μg/ml BSA) at 22° C.for 90 min. At the end of the incubation period, the contents werequickly filtered through a Blue Mat 11740 filter (pretreated with 0.1%polyethylenimine for 3 hours prior to use) by using SKATRON CellHarvester. The filter was then washed with a washing buffer (50 mMTris-HCl (pH 7.4), 5 mM MnCl₂) . The radioactivity was counted by usingan auto gamma counter (Packard RIASTAR 5420A). All data presented arespecific binding defined as that displaceable by 3 μM unlabeledSubstance P.

[0167] (II) Test Result

[0168] All of the following Test Compounds showed more than 80%inhibition rate of ¹²⁵I-BH-Substance P binding to h-NK₁ receptors as hedose of 1 mg/kg.

[0169] Test Compounds:

[0170] The object compounds of the Examples 7, 11, 12, 22, 23, 24-(2),26, 35, 36, 37-(2), (4), (5), (6), (8), 44-(1), (2), (4), (5), (7), 46,47, 51, 52-(1), 53-(1), 54, 55, 58, 59-(1), (3), 62-(1), 67-(4), (5),(6), (7), (13), 71, 72, 73, 74, 75, 76, 77, 81, 82-(1), 82-(4), 82-(5),82-(7), 82-(8), 82-(9), 82-(10), 82-(12), 84-(1) and 86

[0171] B. Emesis in the Ferret

[0172] [I] Test Method

[0173] Individually housed adult male ferrets (Marshall Farms, 1.4 to2.2 kg) were given an i.p. injection of a solution containing a testcompound 30 Min later the emetic responses (retching and vomiting) wereinduced by administration of intra-gastric copper sulfate (40 mg/kg/ml)and observed for the next 30 min. The timing and number of retches andvomits observed were recorded for each animal. An individual animal wastested with at least 10 days between experiments.

[0174] [II] Tess Result

[0175] All of the following Test Compounds showed 100% inhibition rateof emesis in the ferret at the dose of 3.2 and/or 10 mg/kg.

[0176] Test compounds:

[0177] The object compounds of the Examples 12, 22, 23, 24-(2) and37-(5), (6)

[0178] The following Preparations and Examples are given for the purposeof illustrating this invention.

[0179] (to be continued on the next page)

EXAMPLE 1

[0180] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (5 g) and 3-bromopropanol (1.68 g) in N,N-dimethylformamide(40 ml) was heated at 60° C. in the presence of potassium carbonate(4.55 g). After 9 hours, the reaction mixture was poured into water (400ml) and extracted with ethyl acetate. The extract was washed with brineand dried over magnesium sulfate. After evaporation of the solvent, theobtained residue was purified by column chromatography on silica gelusing dichloromethane-methanol (30:1) as an eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (5.36 g) as a powder.

[0181] IR (Neat): 3600-3100, 1625, 1275, 1170, 1128, 898 cm⁻¹

[0182] NMR (DMSO-d₆, δ): 1.6-5.0 (16H, m); 6.6-8.2 (8H, m); 10.84 (1H,s)

[0183] MASS: 514 (M+1), 454

EXAMPLE 2

[0184] The following compound was obtained according to a similar mannerto that of Example 1.

[0185](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(3-hydroxypropyl)piperazine

[0186] IR (Nujol): 3400 (br), 3000-2700, 1625, 1430, 1270, 1120 cm⁻¹

[0187] NMR (DMSO-d₆, δ): 1.55-1.75 (2H, m); 2.05-4.9 (19H, m); 6.5-8.2(6H, m)

[0188] MASS: 503 (M+1)

EXAMPLE 3

[0189] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine(0.3 g), 2-bromo-4′-chloroacetophenone (0.2 g) and potassium carbonate(0.16 g) in N,N-dimethylformamide (5 ml) was stirred at room temperaturefor 1 hour and 20 minutes. The reaction mixture was poured into water(20 ml) and extracted with ethyl acetate. The organic layer was washedwith water and dried over magnesium sulfate. After evaporation of thesolvent, the obtained residue was purified by column chromatography onsilica gel using zoluene-ethyl acetate (4:1) as an eluent. Fractionscontaining objective compound were collected and concentrated underreduced pressure. The obtained product was dissolved in ethyl acetate,treated with 4N hydrogen chloride in ethyl acetate solution and thenevaporated under reduced pressure. The residue was triturated withn-hexane to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chlorophenylcarbonymethyl)-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (0.31 g) as a powder.

[0190] mp: 140° C. (dec.)

[0191] [α]_(D) ²⁰: −22.6° (C=0.5, MeOH)

[0192] IR (Nujol): 3500-3100, 2700-2150, 1690, 1635, 1275, 1100 cm⁻¹

[0193] NMR (DMSO-d₆, δ): 2.9-5.3 (11H, m); 6.4-8.3 (12H, m); 10.7- 11.05(2H, m)

[0194] MASS: 608 (M+1) (free)

EXAMPLE 4

[0195] The following compound was obtained according to a similar mannerto that of Example 3.

[0196] (2R) -1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(5-chloro-2-thienyl)carbonylmethyl-2-(1H-indol-3-ylmethyl)piperazine hydrochloride

[0197] [a]²⁰ _(D): −55.2° (C=0.5, MeOH)

[0198] IR (Neat): 3700-3100, 2700-2150, 1635, 1415, 1275, 1130 cm⁻¹

[0199] NMR (DMSO-d₆, δ): 3.0-5.2 (11H, m); 6.8-8.3 (10H, m); 10.97 (1H,s)

[0200] MASS: 651 (M+1) (free), 614

EXAMPLE 5

[0201] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.3 g), 2-bromo-3′-fluoroacetophenone (0.19 g) and potassiumcarbonate (0.16 g) in N,N-dimethylformamide (5 ml) was stirred at roomtemperature for 1 hour and 20 minutes. The reaction mixture was pouredinto water (20 ml) and extracted with ethyl acetate. The organic layerwas washed with water and dried over magnesium sulfate. Afterevaporation of the solvent, the resulting residue was purified by columnchromatography on silica gel using toluene-ethyl acetate (2:1) as aneluent. The obtained product was dissolved in ethyl acetate (2 ml) andtreated with 4N hydrogen chloride in ethyl acetate solution (164 μl).The resulting precipitate was collected by filtration and dried at 50°C. for 5 hours to give (2R) -1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-fluorophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazinehydrochloride (0.2 g) as a powder.

[0202] mp: 195° C. (dec.)

[0203] [α]_(d) ²⁰: −34.2° (C=0.5, MeOH)

[0204] IR (Nujol): 3200, 2650-2200, 1695, 1655, 1270, 1125 cm⁻¹

[0205] NMR (DMSO-d₆, δ): 3.3-5.3 (11H, m); 6.6-8.3 (12H, m); 10.8-11.4(2H, m)

[0206] MASS: 592 (M+1 ) (free)

[0207] Anal. Calcd. for C₃₀H₂₄F₇N₃O₂·HCl:

[0208] C 57.38; H 4.01; N 6.69

[0209] Found: C 57.23; H 3.79; N 6.49

EXAMPLE 6

[0210] The following compounds were obtained according to a similarmanner to that of Example 5.

[0211] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(3,4-difluorophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl) piperazine hydrochloride

[0212] mp: 171° C. (dec.)

[0213] [α]_(D) ²⁰: −31.6° (C=0.5, MeOH)

[0214] IR (Nujol): 3550-3100, 2650-2150, 1690, 1640, 1510, 1275, 1130cm⁻¹

[0215] NMR (DMSO-d₆, δ): 3.0-5.3 (11H, m); 7.6-8.3 (11H, m; 10.7-11.5(2H, m)

[0216] MASS: 610 (M+1) (free)

[0217] Anal. Calcd. for C₃₀H₂₃F₈N₃O₂·HCl:

[0218] C 55.78; H 3.74; N 6.50

[0219] Found: C 55.54; H 3.72; N 6.41

[0220] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-methylphenylcarbonylmethyl)piperazine hydrochloride

[0221] mp: 203° C. (dec.)

[0222] [α]_(D) ²⁰: −37.4 (C=0.5, MeOH)

[0223] IR (Nujol) 3550-3100, 2650-2150, 1690, 1640, 1280, 1175, 1125cm⁻¹

[0224] NMR (DMSO-d₆, δ): 2.43 (3H, s); 3.1-5.3 (11H, m); 6.8-8.3 (12H,m); 10.8-11.2 (2H, m)

[0225] MASS: 587 (M+1) (free)

[0226] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(3,4-dimethylphenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazine hydrochloride

[0227] mp: 166° C. (dec.)

[0228] [α]_(D) ²⁰: −36.8° (C=0.5, MeOH)

[0229] IR (Nujol): 3600-3150, 2700-2300, 1685, 1635, 1275, 1130 cm⁻¹

[0230] NMR (DMSO-d₆, δ): 2.34 (6H, s); 3.2-5.3 (11H, m); 6.6-8.3 (11H,m); 10.6-11.2 (2H, m)

[0231] MASS: 601 (M+1) (free)

[0232] Anal. Calcd. for C₃₂H₂₉F₆N₃O₂·HCl·1.1H₂O:

[0233] C 58.42; H 4.93; N 6.39

[0234] Found: C 58.46; H 4.90; N 6.27

[0235] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-fluoro-3-methylphenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazine hydrochloride

[0236] [α]_(D) ²⁵: −28.8° (C=0.5, MeOH)

[0237] IR (Nujol): 3600-3100, 2700-2200, 1685, 1635, 1275, 1130 cm⁻¹

[0238] NMR (DMSO-d₆, δ): 2.34 (3H, s); 3.1-5.3 (1H, m); 6.6-8.3 (11H,m); 10.7-11.2 (2H, m)

[0239] MASS: 606 (M+1) (free)

EXAMPLE 7

[0240] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine(228 mg), 1-[4-bromomethyl)phenyl]ethanone (107 mg) and potassiumcarbonate (42 mg) in acetonitrile (2 ml) was refluxed for 4.5 hours.After cooling, the mixture was evaporated in vacuo. Ethyl acetate andwater were added to the residue and the organic layer was separated,washed with brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by column chromatography on silica gelwith a mixture of dichloromethane and methanol as an eluent to give(2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine (0.30 g). To a solution of thispiperazine (0.30 g) in ethyl acetate was added 4N hydrogen chloride inethyl acetate solution (0.13 ml) and the whole was evaporated in vacuo.The residue was triturated with a mixture of ethyl acetate and ether togive(2R)-4-(4-acetylbenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (283.5 mg) as a powder.

[0241] mp: 172° C. (dec.)

[0242] [α]_(D) ²⁸: −30.0° (C=0.27, MeOH)

[0243] IR (Nujol): 3350, 1675, 1655, 1635, 1610, 1275 cm⁻¹

[0244] NMR (CDCl₃, δ) 2.36-5.60 (11H, m); 6.10-9.30 (13H, m); 12.90 (1H,br s)

[0245] MASS: 588 (M) (free)

EXAMPLE 8

[0246] A mixture of(2R)-1-[3,5-bis(trifloromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine(0.3 g), 2-bromo-4′-dimethylaminoacetophenone (0.2 g) and potassuumcarbonate (0.16 g) in N,N-dimethylformamide (5 m,) was stirred at roomtemperature for 2 hours. The reaction mixture was poured into water (20ml) and extracted with ethyl acetate. The organic layer was washed withwater and dried over magnesium sulfate. Affer evaporation of thesolvent, the resulting residue was purified by column chromatography onsilica gel using toluene-ethyl acetate (2:1) as an eluent. Fractionscontaining objective compound were collected and evaporated underreduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-dimethylaminophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl]piperazine(0.26 g).

[0247] mp: 185° C. (dec.)

[0248] [α]_(D) ²⁰: −44.6° (C=0.5, MeOH)

[0249] IR (Nujol): 3300, 1650, 1590, 1290-1150 cm⁻¹

[0250] NMR (DMSO-d₆, δ) 2.0-4.9 (1H, m); 3.03 (6H, s); 6.55-8.2 (12H,m); 10.80 (1H, s)

[0251] MASS: 617 (M+1)

EXAMPLE 9

[0252] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg), 4-nitrobenzyl chloride (158 mg) andtriethylamine (268 μl) in tetrahydrofuran (5 ml) was refluxed overnight.After cooling, the precipitates were filtered off and the filtrate wasevaporated in vacuo. The residue was purified by column chromatographyon silica gel with a mixture of toluene and ethyl acetate as an eluentto give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (169.8 mg).

[0253] IR (Neat): 3100-2750, 1770, 1730, 1635, 1520, 1440, 1340, 1275,1130 cm⁻¹

[0254] NMR (DMSO-d₆, δ): 2.10-5.40 (11H, m); 6.85-8.30 (10H, m)

[0255] MASS: 621 (M+1)

EXAMPLE 10

[0256] The following compound was obtained according to a similar mannerto that of Example 9.

[0257](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-nitrobenzyl)piperazine

[0258] IR (Neat): 3100-2750, 1635, 1515, 1430, 1340, 1275, 1130 cm⁻¹

[0259] NMR (DMSO-d₆, δ): 2.00-4.85 (17H, m); 6.50-8.10 (10H, m)

[0260] MASS: 580 (M+1)

EXAMPLE 11

[0261] To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.25 g) and 4-acetylbenzoicacid (0.09 g) in dichloromethane (8 ml) was added triethylamine (0.2 ml)at room temperature. 2-Chloro-1-methylpyridinium iodide (0.17 g,) wasadded, and the mixture was stirred a room temperature for 2.5 hours. Theresulting mixture was concentrated under reduced pressure and theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with aqueous sodium bicarbonate solution and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography using ethyl acetate - n-hexane (1:1)as an eluent to afford (2R)-4-(4-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.31 g).

[0262] NMR (DMSO-d₆, δ): 1.9-2.4 (8H, m); 2.5-5.2 (10H, m); 6.4-8.2(10H, m)

[0263] MASS: 591 (M+1)

EXAMPLE 12

[0264] To a mixture of (2R)-1-3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg) and4-acetylbenzoic acid (57 mg) in dichloromethane (5 ml) was addedtriethylamine (171 μl) at room temperature. 2-Chloro-1-methylpyridiniumiodide (107 mg) was added, and the mixture was stirred at roomtemperature for 1.5 hours. The resulting mixture was washed successivelywith aqueous 0.1N hydrogen chloride solution, aqueous saturated sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate.After evaporation of the solvent, the residue was purified by columnchromatography using toluene-ethyl acetate (5:1) as an eluent to give(2R)-4-(4-acetylbenzoyl)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (158 mg).

[0265] [α]_(D) ²⁰: 11.2° (C=0.5, MeOH)

[0266] IR (Neat): 3100-2850, 1685, 1630, 1440, 1275, 1130 cm⁻¹

[0267] NMR (DMSO-d₆, δ) 2.15-5.15 (9H, m); 2.62 (3H, s); 6.8-8.3 (10H,m)

[0268] MASS: 633 (M+2), 631

[0269] Anal. Calcd. for C₂₉H₂₂F₆Cl₂N₂O₃:

[0270] C 55.17; H 3.51; N 4.44

[0271] Found: C 55.22; H 3.53; N 4.28

EXAMPLE 13

[0272] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine fumarate (785 mg) was added to a mixture of 2N sodiumhydroxide solution (5 ml) and ethyl acetate. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated in vacuo to give(2R)-1-[3,5-bis(trifluoroethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine. A solution of this piperazine in N,N-dimethylformamide (7ml) was added to a mixture of 2-acetylbenzoic acid (230 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295 mg) and1-hydroxybenzotriazole (208 mg) in N,N-dimethylformamide (3 ml) and thewhole was stirred at room temperature overnight. The mixture was pouredinto a saturated sodium hydrogen carbonate solution (78 ml) and theresulting precipitates were filtered off. The filtrate was evaporated invacuo to give(2R)-4-(2-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.45 g) as a powder.

[0273] mp: 82-85°0 C.

[0274] [α]_(D) ²⁹: −22.7 (C=0.33, MeOH)

[0275] IR (CHCl₂): 1750, 1635, 1615 cm⁻¹

[0276] NMR (CDCl₃, δ) 1.75-5.40 (18H, m); 6.40-8.10 (10H, m)

[0277] MASS: 591 (M)

EXAMPLE 14

[0278] The following compound was obtained according to a similar mannerto that of Example 13.

[0279] (2R)-4-(3-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)piperazine

[0280] mp: 155.5-157° C.

[0281] [α]_(D) ²⁴: 5.8° (C=0.26, MeOH)

[0282] IR (Nujol): 1688, 1630 cm⁻¹

[0283] NMR (CDCl₃, δ): 2.05-2.32 (6H, m); 2.63 (3H, s); 2.70-5.40 (9H,m); 6.40-8.15 (10H, m)

[0284] MASS: 592 (M+1)

EXAMPLE 15

[0285] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine (250 mg),2-methoxyphenylacetic acid (92 mg) and 1-hydroxybenzotriazole (75 mg) indichloromethane (8 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg) atroom temperature. After 3 hours, the reaction mixture was poured intoaqueous sodium bicarbonate solution and extracted with dichloromethane.The extract was washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue was purified by columnchromatography on silica gel using ethyl acetate - n-hexane (1:1.5) asan eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methoxyphenylmethylcarbonyl)piperazine (290 mg) as a powder.

[0286] NMR (DMSO-d₆, δ): 2.6-5.0 (14H, m); 6.4-8.2 (12H, m); 10.8 (1H,m)

[0287] MASS: 604 (M+1)

EXAMPLE 16

[0288] The following compounds were obtained according to a similarmanner to that of Example 15.

[0289] (1) (2R)-4-(3-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine

[0290] mp: 186-187.5° C.

[0291] [α]_(D) ²⁹: 4.2° (C=0.29, MeOH)

[0292] IR (Nujol): 3260, 1690, 1633, 1600, 1275 cm⁻¹

[0293] NMR (CDCl₃, δ): 1.55-5.46 (12H, m); 6.55-8.50 (13H, m)

[0294] MASS: 602 (M)

[0295] (2) (2R)-4-(2-Acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine

[0296] mp: 190-192° C.

[0297] [α]_(D) ²⁸: −2.1° (C=0.28, MeOH)

[0298] IR (Nujol): 3300, 2700, 1750, 1720, 1635, 1630, 1275 cm⁻¹

[0299] NMR (CDCl₃, δ): 1.46-5.45 (12H, m); 6.54-8.25 (13H, m)

[0300] MASS: 602 (M)

EXAMPLE 17

[0301] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carboxymethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.4 g) and thiomorpholine (0.08 g) in dryN,N-dimethylformamide (4 ml) were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g) and1-hydroxybenzotriazole (0.29 g) at room temperature. After 3 hours, thereaction mixture was poured into aqueous sodium bicarbonate solution (40ml) and the resulting precipitate was collected by filtration. The crudeproduct obtained was purified by column chromatography on silica gelusing toluene-ethyl acetate (1:2) as an eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(thiomorpholinocarbonylmethyl)piperazine (0.42 g).

[0302] [α]_(D) ¹⁹: −10.0° (C=0.5, MeOH)

[0303] IR (Neat): 3650-3100, 1634, 1274, 1170, 1122, 898 cm⁻¹

[0304] NMR (DMSO-d₆, δ): 2.00-5.00 (19H, m); 6.60-8.20 (8H, m); 10.86(1H, s)

[0305] MASS: 599 (M+1)

EXAMPLE 18

[0306] The following compound was obtained according to a similar mannerto that of Example 17.

[0307](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[(4-(4-fluorophenyl)-1-piperazinyl)carbonylmethyl]-2- (1H-indol-3-ylmethyl) piperazine hydrochloride

[0308] mp: 183° C. (dec.)

[0309] [α]_(D) ²⁵: −24.0° (C=0.5, MeOH)

[0310] IR (Nujol): 3600-3100, 2650-2150, 1680-1580, 1510, 1275, 1130cm⁻¹

[0311] NMR (DMSO-d₆, δ): 3.05-5.15 (19H, m); 6.6-8.3 (12H, m); 10.40(2H, br s); 11.02 (1H, s)

[0312] MASS: 676 (M+1) (free)

EXAMPLE 19

[0313] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carboxymethyl)-2- (1H-indol-3-ylmethyl)piperazine (200 mg) and 4-cyclopentylpiperazine (60 mg) in dryN,N-dimethylformamide (5 ml) were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82 mg) and1-hydroxybenzotriazole (58 mg) at room temperature. After 7 hours, thereaction mixture was poured into water (30 ml) and extracted with ethylacetate. The extract was washed with water and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified bycolumn chromatography on silica gel using dichloromethane-methanol(10:1) as an eluent and then treated with 4N hydrogen chloride in ethylacetate solution (80 μl) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(4-cyclopentyl-1-piperazinyl)carbonylmethyl]-2- (1H-indol-3-ylmethyl)piperazine hydrochloride (40mg).

[0314] mp: 270° C. (dec.)

[0315] [α]_(D) ²⁵: −24.2° (C=0.5, MeOH)

[0316] IR (Nujol): 3270, 2430-2150, 1630, 1275, 1180, 1125 cm⁻¹

[0317] NMR (DMSO-d₆, δ): 1.45-5.0 (28H, m), 6.55-8.25 (8H, m); 10.90(1H, s); 11.21 (2H, br s)

[0318] MASS: 650 (M+1) (free)

[0319] Anal. Calcd. for C₃₃H₃₇F₆N₅O₂·HCl:

[0320] C 57.77; H: 5.58; NT 10.21

[0321] Found : C 57.91; H 5.64; N 10.18

EXAMPLE 20

[0322] A solution of methanesulfonyl chloride (1.1 g) in dicloromethane(4 ml) was added to a stirred solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.99 g) and triethylamine (1.1 g) in dichloromethane (50 ml)at ice-bath temperature over a 20-minute period. After being stirred atthe same temperature for 1 hour, the reaction mixture was diluted withdichloromethane (50 ml) and then washed with water and aqueous sodiumbicarbonate solution. The dichloromethane layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel usingdichloromethane-methanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trfluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (4.31 g) as a powder.

[0323] MASS: 592 (M+1)

EXAMPLE 21

[0324] The following compound was obtained according to a similar mannerto that of Example 20.

[0325](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(3-methylsulfonyloxypropyl)piperazine

[0326] IR (Nujol): 2950-2700, 1635, 1430, 1350, 1275, 1165, 1125 cm⁻¹

[0327] NMR (DMSO-d₆, δ) : 1.8-4.95 (19H, m); 3.19 (3H, s); 4.31 (2H, t,J=6.2Hz); 6.95-8.2 (6H, m)

[0328] MASS: 581 (M−1)

EXAMPLE 22

[0329] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine(0.2 g), 3-azabicyclo[3.2.2]nonane (0.05 g) and triethylamine (0.09 ml)in N,N-dimethylformamide (1 ml) was heated at 80° C. After 6 hours, thereaction mixture was poured into water (10 ml) andd the resultingprecipitate was collected by filtration. The crude product was dissolvedin ethanol (2 ml) and then treated with 17.6% hydrogen chloride inethanol solution (0.3 ml) to give(2R)-4-[3-(3-azabicyclo(3.2.2]non-3-yl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine dihydrochloride (0.12 g) as a powder.

[0330] mp: 194-202° C.

[0331] [α]_(D) ¹⁹: −6.0° (C=0.5, MeOH)

[0332] IR (Nujol): 3600-3100, 2750-2000, 1680-1550, 1275, 1172, 1126,900 cm⁻¹

[0333] NMR (DMSO-d₆, δ): 1.50-5.20 (29H, m); 6.60-8.25 (8H, m); 9.80(1H, br s); 10.96 (1H, s); 11.60 (1H, br s)

EXAMPLE 23

[0334] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine(0.2 g), thiomorpholine (0.042 g) and triethylamine (0.09 ml) in dryacetonitrile (2 ml) was stirred at 90° C. for 15 hours. The reactionmixture was concentrated under reduced pressure and the resultingresidue was partitioned between ethyl acetate and water. The organiclayer was washed with brine and dried over magnesium sulfate. Afterevaporation of the solvent, the residue was purified by columnchromatography on silica gel using ethyl acetate-methanol (10:1) as aneluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine. The product obtained was dissolved in ethanol and treatedwith 17.6% hydrogen chloride in ethanol solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (0.19 g) as a powder.

[0335] [α]_(D) ²⁰: −4.6 (C=0.5, MeOH)

[0336] IR (Nujol): 3650-3050, 2750-1980, 1635, 1274, 1170, 1123, 900cm⁻¹

[0337] NMR (DMSO-d₆, δ): 2.20-5.20 (23H, m); 6.50-8.25 (8H, m); 10.96(1H, s); 11.00-11.90 (2H, m)

[0338] MASS: 599 (M+1) (free)

[0339] (2R)-4-(3-Thiomorpholinopropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2- (1H-indol-3-ylmethyl)piperazine dimaleate

[0340] mp: 110-115° C.

[0341] [α]_(D) ²¹: −14.2° (C=0.25, MeOH)

[0342] IR (Nujol): 3350, 2720, 1690, 1620, 1605, 1280, 1130 cm⁻¹

[0343] NMR (DMSO-d₆, δ): 1.70-5.12 (23H, m), 6.14 (4H, s), 6.55-8.32(8H, m), 10.90 (1H, s)

EXAMPLE 24

[0344] The following compounds were obtained according to a similarmanner to that of Example 23.

[0345] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-morpholinopropyl)piperazinedihydrochloride

[0346] mp: 265° C. (dec.)

[0347] [α]_(D) ³¹: −6.0° (C=0.5, MeOH)

[0348] IR (Nujol): 3650-3100, 2750-2200, 1655, 1275, 1120 cm⁻¹

[0349] NMR (DMSO-d₆, δ): 2.2-2.45 (2H, m); 3.0-5.25 (21H, m); 6.55-8.25(8H, m); 10.98 (1H, s); 11.1-12.85 (2H, m)

[0350] MASS: 583 (M+1) (free)

[0351] Anal. Calcd. for C₂₉H₃₂F₆N₄O₂·2HCl·0.4H₂O:

[0352] C 52.56; H 5.29; N 8.45

[0353] Found: C 52.54; H 5.33; N 8.25

[0354] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride

[0355] mp: 272° C. (dec.)

[0356] [α]_(D) ³¹: −11.6° (C=0.5, MeOH)

[0357] IR (Nujol): 3650-3100, 2750-2650, 1635, 1270, 1120 cm⁻¹

[0358] NMR (DMSO-d₆, δ): 2.1-2.5 (8H, m); 2.7-5.2 (21H, m); 6.6-8.25(6H, m); 11.15-11.75 (2H, m)

[0359] MASS: 588 (M+1) (free)

EXAMPLE 25

[0360] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (200 mg) and 1,2,3,4-tetrahydroisoquinoline (90 mg) inmethanol (3 ml) was stirred for 1.5 hours at reflux temperature. Thereaction mixture was evaporated under reduced pressure and the residuewas purified by column chromatography on silica gel using ethylacetate-methanol (10:1) as an eluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-[1,2,3,4-tetrahydroisoquinolin-2-yl]propyl]piperazine(167 mg) as a powder.

[0361] [α]_(D) ²⁰: −9.6° (C=0.5, MeOH)

[0362] IR (Neat): 3260, 1630, 1430, 1380, 1350, 1270 cm⁻¹

[0363] NMR (DMSO-d₆, δ): 1.60-4.93 (21H, m); 6.60-8.37 (12H, m); 10.85(1H, s)

[0364] MASS: 629 (M+1)

EXAMPLE 26

[0365] The following compound was obtained according to a similar mannerto that of Example 25.

[0366](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)propyl]piperazine

[0367] [α]_(D) ¹⁸: −9.0° (C=0.5, MeOH)

[0368] IR (Neat): 3260, 1630, 1430, 1350, 1275 cm⁻¹

[0369] NMR (DMSO-d₆, δ): 1.55-4.97 (21H, m); 6.30-8.24 (10H, m); 10.85(1H, s)

[0370] MASS: 635 (M+1)

EXAMPLE 27

[0371] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine(150 mg) and 4-cyano-4-phenylpiperidine hydrochloride (70 mg) inmethanol (5 ml) was stirred at reflux temperature in the presence ofsodium carbonate (100 mg). After 2 hours, the reaction mixture wasevaporated under reduced pressure. The residue was extracted with ethylacetate and the extract was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel using ethylacetate-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(4-cyano-4-phenylpiperidino)propyl]-2-(1H-indol-3-ylmethyl)piperazine (89 mg) as a powder.

[0372] [α]_(D) ²⁰: −19.2° (C=0.5, MeOH)

[0373] NMR (DMSO-d₆, δ): 1.52-4.96 (23H, m); 6.60-8.26 (13H, m); 10.85(1H, s)

[0374] MASS: 682 (M+1)

EXAMPLE 28

[0375] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine(200 mg) and spiro[indan-1,4′-piperidine] (70 mg) in acetonitrile (3 ml)was refluxed for 1.5 hours. The reaction mixture was evaporated underreduced pressure and then the residue was purified by columnchromatography on silica gel using dichloromethane-methanol (10:1) as aneluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(spiro[indan-1,4′-piperidine]-1′-yl)propyl]-2-(1H-indol-3-ylmethyl) piperazine (208 mg)as a powder.

[0376] [α]_(D) ²²: −21.4° (C=1.0, MeOH)

[0377] IR (Neat): 3260, 1630, 1435, 1380, 1350, 1275 cm⁻¹

[0378] NMR (DMSO-d₆, δ): 1.45-5.00 (27H, m); 6.62-8.28 (12H, m); 10.88(1H, s)

[0379] MASS: 683 (M+1)

EXAMPLE 29

[0380] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (157 mg), ammonium chloride (15.7 mg) and iron powder (157mg) in a mixture of ethanol (5 ml) and water (1.25 ml) was refluxed for1.5 hours. After cooling, the precipitates were filtered off and thefiltrate was evaporated in vacuo. The residue was purified by columnchromatography on silica gel with a mixture of toluene and ethyl acetateas an eluent to give(2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (128.4 mg).

[0381] IR (Neat): 3350, 2970-2700, 1630, 1515, 1460, 1430, 1275, 1130cm⁻¹

[0382] NMR (DMSO-d₆, δ): 1.95-5.05 (13H, m); 6.50-8.25 (10H, m)

[0383] MASS: 592 (M+2), 590 (M)

EXAMPLE 30

[0384] The following compound was obtained according to a similar mannerto that of Example 29.

[0385] (2R)-4-(4-Aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine

[0386] IR (Neat): 3450, 3300, 3100-2650, 1625, 1515, 1435, 1275, 1125cm⁻¹

[0387] NMR (DMSO-d₆, δ): 1.90-4.80 (17H, m); 4.98 (2H, s); 6.40-8.20(10H, m)

[0388] MASS: 550 (M+1)

EXAMPLE 31

[0389] Piridine (23 μl) and acetyl chloride (16 μl) were successivelyadded to a solution of(2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (113 mg) and the whole was stirred at room temperature for1.5 hours. The mixture was poured into water and the separated oil wasextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby column chromatography on silica gel with a mixture of toluene andethyl acetate as an eluent to give(2R)-4-(4-acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (98.3 mg). The obtained piperazine was dissolved in ethylacetate. 4N Hydrogen chloride in ethyl acetate solution (43 μl) wasadded to the solution and the mixture was evaporated in vacuo. Theresidue was triturated with n-hexane to give(2R)-4-(4-acetylaminobenzy)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl) piperazinehydrochloride (92 mg).

[0390] [α]_(D) ²⁰: −11.8° (C=0.5,MeOH)

[0391] IR (Neat): 3600-3150, 2750-2100, 1635, 1600, 1525, 1415, 1270,1130 cm⁻¹

[0392] NMR (DMSO-d₆, δ): 2.07 (3H, s); 2.85-5.15 (11H, m); 6.80-8.30(10H, m); 10.13 (1H, s)

[0393] MASS: 32 (M+1) (free)

EXAMPLE 32

[0394] The following compound was obtained according to a similar mannerto that of Example 31.

[0395] (2R)-4-(4-Acetylaminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine hydrochloride

[0396] [α]_(D) ²⁵: −23.2° (C=0.5, MeOH)

[0397] IR (Nujol): 3650-3100, 2750-2100, 1640, 1600, 1530, 1275, 1170,1130 cm⁻¹

[0398] NMR (DMSO-d₆, δ): 1.95-2.10 (9H, m); 2.80-5.05 (11H, m);6.50-8.30 (10H, m); 10.17 (1H, s); 11.00-11.40 (1H, m)

[0399] MASS: 592 (M+1) (free)

EXAMPLE 33

[0400](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(thiomorpholinocarbonylmethyl)piperazine was converted to the corresponding hydrochloride by treatmentwith 17.6% hydrogen chloride in ethanol solution.

[0401] IR (Nujol): 3650-3100, 2750-1980, 1638, 1276, 1171, 1129, 900cm⁻¹

[0402] NMR (DMSO -d₆, δ): 2.55-5.15 (19H, m); 6.60-8.25 (8H, m); 10.99(1H, s)

[0403] MASS: 599 (M+1) (free)

Preparation 1

[0404] A mixture of formaldehyde (37% in water, 20.7 ml) and morpholine(17.1 ml) was adjusted to pH 3.5 with diluted sulfuric acid. Propargylalcohol (10 g), potassium iodide 0.3 g), and copper (II) sulfate (0.14g) were added to the solution and the whole was stirred at 95° C. for 6hours. After cooling, the insoluble material was removed by filtrationand the pH of the filtrate was adjusted to 9 with 24% sodium hydroxidesolution. Brine (100 ml) was added to the solution and the solution wasextracted with a mixture of ethyl acetate and ethanol (10:1) eight timesand then with n-butanol six times. The combined extract was dried overmagnesium sulfate and evaporated in vacuo. The residue was distilled inreduced pressure to give 4-morpholino-2-butyn-1-ol (14.03 g).

[0405] bp: 124-131° C.

[0406] IR (Neat): 3350, 2850, 1105, 1000 cm⁻¹

[0407] NMR (CDCl₃, δ): 2.18 (1H, br s), 2.57 (4H, t, J=4.7Hz), 3.31 (2H,t, J=1.9Hz), 3.75 (4H, t, J=4.7Hz), 4.30 (2H, t, J=1.9Hz)

[0408] MASS: 156 (M+1)

Preparation 2

[0409] The following compound was obtained according to a similar mannerto that of Preparation I with the exception of purification by columnchromatography on silica gel using a mixture of ethyl acetate andmethanol (30:1) as an eluent instead of distillation in reducedpressure.

[0410] 4- Thiomorpholino-2-butyn-1-ol

[0411] IR (Neat): 3350, 2900, 2800, 4920, 1330, 1115, 1100 cm⁻¹

[0412] NMR (CDCl₃, δ): 1.93 (1H, br s), 2.65-2.90 (8H, m), 3.32 (2H, tJ=1.9Hz), 4.30 (2H, t, J=1.9Hz)

[0413] MASS: 172 (M+1)

Preparation 3

[0414] Thionyl chloride (2.1 ml) was added to a solution of4-morpholino-2-butyn-1-ol (1.47 g) in dichloromethane (10 ml) with icebath cooling. After stirring for 0.5 hour, the solution was evaporatedin vacuo. The residue was triturated with ethyl acetate to give4-morpholino-2-butynyl chloride hydrochloride (1.91 g).

[0415] mp: 162-165° C.

[0416] IR (Nujol): 2640, 2510, 2450, 2350 cm⁻¹

[0417] NMR (DMSO-d₆, δ): 3.31 (4H, br s), 3.92 (4H, br s), 4.21 (2H, t,J=1.9Hz), 4.57 (2H, t, J=1.9Hz), 12.23 (1H, br s)

[0418] MASS: 174 (M) (free)

Preparation 4

[0419] The following compound was obtained according to a similar mannerto that of Preparation 3.

[0420] 4-Thiomorpholino-2-butynyl chloride hydrochloride

[0421] m.p: 185-187° C.

[0422] IR (Nujol): 2600, 2450, 2380, 1280, 1260, 1160, 915 cm⁻¹

[0423] NMR (DMSO-d₆, δ): 2.58-4.00 (8H, m), 4.21 (2H, t, J=2.0Hz), 4.58(2H, t, J=2.0Hz), 12.08 (1H, br s)

[0424] MASS: 190 (M) (free)

Preparation 5

[0425] A mixture of 4-chloro-1-(4-fluorophenyl-1-butanone (500 mg),ethylene glycol (247 mg) and catalytic amount of p-toluenesulfonic acidmonohydrate in benzene (5 ml) was refluxed for 20 hours with continuousremoval of water using Dean-Stark apparatus. After cooling, the solutionwas washed sucessively with 1N NaOH solution and brine, dried overmagnesium sulfate, and evaporated in vacuo to give 4-chloro-1-(4-fluorophenyl)-1-butanone cyclic ethylene acetal (613.2 m.g) as an oi.

[0426] IR (Neat): 2950, 2870, 1600, 1500, 1220, 1030 cm⁻¹

[0427] NMR (DMSO-d₆, δ): 1.60-1.80 (2H, m), 1.90-2.00 (2H, m), 3.61 (2H,t, J=6.5Hz), 3.70-4.10 (4H, m), 7.10-7.50 (4H, m,)

[0428] MASS: 245 (M+1), 209

EXAMPLE 34

[0429] A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl) piperazine(1.0 g) and 3-bromopropanol (330 mg) in N,N-dimethylformamide (2.5 ml)was stirred at room temperature in the presence of powdered potassiumcarbonate (444 mg). After 17 hours, the reaction mixture was dilutedwith ethyl acetate (30 ml) and then washed successively with water andbrine, and dried over magnesium sulfate. Evaporation of the solvent invacuo qave (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-napthylmethyl)piperazine (1.19 g).

[0430] IR (Neat): 3425, 1635, 1430, 1340, 1275, 1170, 1130 cm⁻¹

[0431] NMR (CDCl₃, δ): 1.50-5.28 (16H, mn), 7.40-7.93 (10H, m)

[0432] MASS: 528 (M+1)

EXAMPLE 35

[0433] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl) piperazine(200 mg) and 1-(4-chloro-2-butynyl) morpholine hydrochloride (95 mg) inN,N-dimethylformamide (0.5 ml) was stirred at room temperature in thepresence of powdered potassium carbonate (177 mg). After 17 hours, thereaction mixture was diluted with ethyl acetate (30 ml) and then washedsuccessvely with water and brine, and dried over magnesium sulfate.After evaporation of the solvent in vacuo, the resulting residue waspurified by column chromatography on silica gel using ethyl acetate asan eluent. The product obtained was dissolved in ethyl acetate andtreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2-butynyl)-2-(2-naphthylmethyl)piperazine dihydrochloride (257 mg).

[0434] [α]_(D) ²¹: −21.5° (C=0.5, MeOH)

[0435] IR (Nujol): 3350, 2550, 1630, 1275 cm⁻¹

[0436] NMR (DMSO-d₆, δ): 2.80-5.31 (21H, m), 7.0-8.28 (10H, m)

[0437] MASS: 604 (M+1) (free)

EXAMPLE 36

[0438] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (150 mg) and 1-(4-chloro-2-butynyl)morpholinehydrochloride (63 mg) in N,N-dimethylformamide (0.5 ml) was stirred atroom temperature in the presence of powdered potassium carbonate (160mg). After 17 hours, the reaction mixture was diluted with ethyl acetate(30 ml) and then washed successively with water and brine, and driedover magnesizm sulfate. After evaporation of the solvent in vacuo, theresulting residue was purified by column chromatography on silica gelusing a mixture of ethyl acetate and methanol (10:1) as an eluent togive(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine. The product obtained was dissolved in ethyl acetate andtreated with 4N hydrogen chloride in ethyl acetate solution to givedichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine dihydrochloride(155 mg).

[0439] [α]_(D) ²⁰: −3.9° (C=0.5, MeOH)

[0440] IR (Neat): 3400, 2350, 1640, 1425, 1275 cm⁻¹

[0441] NMR (DMSO-d₆, δ): 2.91-5.20 (21H, m), 7.0-8.26 (6H, m)

[0442] MASS: 629 (M+1) (free)

EXAMPLE 37

[0443] The following compounds were obtained according to a similarmanner to that of Example 7.

[0444] (1) (2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinedihydrochloride

[0445] mp: 165-169° C.

[0446] [α]_(D) ²¹: −0.4° (C=0.26, MeOH)

[0447] IR (Nujol): 3350, 2550, 2320, 1635, 1550, 1270, 1120 cm⁻¹

[0448] NMR (DMSO-d₆, δ): 2.80-5.25 (21H, m), 6.56-8.30 (8H, m), 10.96(1H, s)

[0449] MASS: 593 (M) (free)

[0450] (2) (2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazinedihydrochloride

[0451] mp: 155-162° C.

[0452] [α]_(D) ²¹: −11.5° (C=0.26, MeOH)

[0453] IR (Nujol): 3350, 2650, 2300, 1655, 1640, 1275, 1120 cm⁻¹

[0454] NMR (DMSO-d_(6, δ):) 2.02-2.30 (7H, m,), 2.64-5.30 (20H, m),6.60-8.30 (6H, m)

[0455] MASS: 582 (M) (free)

[0456] (3) (2R)-4-(4-Thiomorpholino-2-butynyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazinedihydrochloride

[0457] mp: 162-170° C.

[0458] [α]_(D) ²²: −9.4° (C=0.27, MeOH)

[0459] IR (Nujol): 3350, 2650, 2320, 1655, 1640, 1275, 1125 cm⁻¹

[0460] NMR (DMSO-d₆, δ): 2.04-2.35 (7H, m), 2.65-5.25 (20H, m),6.57-8.28 (6H, m)

[0461] MASS: 598 (M) (free)

[0462] (4) (2R)-4-(4-Thiomorpholino-2-butynyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinedihydrochloride

[0463] mp: 166-170° C.

[0464] [α]_(D) ²²: −1.5° (C=0.26, MeOH)

[0465] IR (Nujol): 3350, 2650, 2300, 1635, 1275, 1125 cm⁻¹

[0466] NMR (DMSO-d₆, δ): 2.58-5.30 (21H, m), 6.54-8.30 (8H, m), 10.98(1H, br s), 12.10 (2H, br s)

[0467] MASS: 609 (M) (free)

[0468] (5) (2R)-4-(2-Morpholinoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrocloride

[0469] mp: 223-228° C.

[0470] [α]_(D) ^(27.2): −13.0° (C=0.28, MeOH)

[0471] IR (Nujol): 3350, 2550, 1630, 7450, 1275, 1120 cm⁻¹

[0472] NMR (DMSO-D₆, δ): 1.95-5.25 (27H, m), 6.50-8.32 (6H, m),10.80-11.90 (2H, br m)

[0473] MASS: 558 (M) (free)

[0474] (6) (2R)-4-(2-Thiomorpholinoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinedihydrochloride

[0475] mp: 170-182° C.

[0476] [α]_(D) ^(28.5): −4.5° (C=0.39, MeOH)

[0477] IR (Nujol): 3350, 2600, 1640, 1275, 1125 cm⁻¹

[0478] NMR (DMSO-d₆, δ): 2.60-5.30 (21H, m), 6.50-8.30 (8H, m), 10.96(1H, s), 11.10-12.10 (2H, br m)

[0479] MASS: 585 (M) (free)

[0480] (7) (2R)-4-(2-Morpholinoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinedihydrochloride

[0481] mp: 170-176° C.

[0482] [α]_(D) ^(28.5): −3.0° (C=0.30, MeOH)

[0483] IR (Nujol): 3350, 2570, 1640, 1275, 1125 cm⁻¹

[0484] NMR (DMSO-d₆, δ): 2.60-5.30 (21H, m), 6.55-8.40 (8H, m), 10.95(1H, s), 11.10-12.04 (2H, br m)

[0485] MASS: 569 (M) (free)

[0486] (8) (2R)-4-(2-Thiomorpholinoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazinedihydrochloride

[0487] mp: 261.5° C.

[0488] [α]_(D) ^(28.5): −1.9° (C=0.29, DMF)

[0489] IR (Nujol): 3350, 2350, 1640, 1275, 1130 cm⁻¹

[0490] NMR (DMSO-d₆, δ): 2.00-5.30 (27H, m), 6.60-8.30 (6H, m),1.60-12.00 (2H, br m)

[0491] MASS: 574 (M) (free)

EXAMPLE 38

[0492] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (300 mg), 4-chloro-1-(4-fluorophenyl)-1-butanone cyclicethylene acetal (161 mg), potassium carbonate (182 mg), and potassiumiodide (109 mg) in acetonitrile (10 ml) was refluxed for 20 hours. Aftercooling, the insoluble material was removed by filtration and thefiltrate was evaporated in vacuo. The residue was purified by columnchromatography on silica gel with a mixture of toluene and ethyl acetateas an eluent to give(2R)-4-[4,4-ethylenedioxy-4-(4-fluorophenyl)butyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine as apowder. This compound was further purified by washing with diisopropylether.

[0493] mp: 145-146° C.

[0494] IR (Nujol): 3200, 1620, 1600, 1275, 1120 cm⁻¹

[0495] NMR (DMSO-d₆, δ): 1.35-1.55 (2h, m), 1.80-4.90 (17H, m),6.55-8.20 (12H, m), 10.87 (1H, br s)

[0496] MASS: 664 (M+1)

EXAMPLE 39

[0497] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carboxymethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.2 g) and 3-azabicyclo3.2.2]nonane (0.05 g) in dryN,N-dimethylformamide (2 ml) were added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.082 g)and 1-hydroxybenzotriazole (0.058 g) at room temperature. After 6 hours,the reaction mixture was poured into aqueous sodium bicarbonate solution(20 ml) and the resulting precipitate was collected by filtration. Thecrude product obtained was purified by column chromatography on silicagel using toluene-ethyl acetate (1:2) as an eluent and treated with77.6% hydrogen chloride in ethanol solution to give(2R)-4-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinehydrochloride (0.2 g) as a white powder.

[0498] [α]_(D) ²⁰: −32.0° (C=0.5, MeOH)

[0499] IR (Nujol): 3650-3100, 2750-2000, 1637, 1276, 1172, 1130, 900cm⁻¹

[0500] NMR (DMSO-d₆, δ): 1.50-1.75 (8H, m), 2.07 (2H, br s), 3.15-5.10(15H, m), 6.60-8.25 (8H, m), 10.15 (1H, br s), 11.00 (1H, s)

[0501] MASS: 621 (M+1) (free)

EXAMPLE 40

[0502] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-carboxybenzyl)-2-(1H-indol-3-ylmethyl)piperazine (150 mg) and diethylamine hydrochloride (28 mg) in drydichloromethane (5 ml) were added a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (40 mg) in dichloromethane(1 ml) and 1-hydroxybenzotriazole (34 mg) at room temperature. After 5hours, the reaction mixture was poured into aqueous sodium bicarbonatesolution (20 ml). The organic layer was separated and washed with brineand dried over magnesium sulfate. The crude product obtained waspurified by column chromatography on silica gel using ethyl acetate -n-hexane (4:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(N,N-diethylaminocarbonyl)benzyl]-2-(1H-indol-3-ylmethyl)piperazine (107 mg) as a powder.

[0503] [α]_(D) ²¹: −40.3° (C=0.5, MeOH)

[0504] IR (Neat): 3250, 1620, 1430, 1275, 1130 cm⁻¹

[0505] NMR (CDCl₃, δ): 1.10-5.00 (25H, m) 6.40-8.00 (8H, m), 9.14 (1H,s)

[0506] MASS: 645 (M+1)

EXAMPLE 41

[0507] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.1 g) and triethylamine (425 mg) in dichloromethane (10 ml)was added dropwise methanesulfonyl chloride (252 mg) at ice-bathtemperature. After 2 hours, the reaction mixture was washed with waterand then dried over magnesium sulfate. After evaporation of the solvent,the resulting residue was chromatographed on silica gel using ethylacetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (988 mg).

[0508] IR (Neat): 1635, 1430, 1350, 1280, 1170, 1130 cm⁻¹

[0509] NMR (CDCl₃, δ): 1.59 (3H, s), 1.90-5.28 (15H, m), 7.40-7.90 (10H,m)

[0510] MASS: 603 (M+1)

EXAMPLE 42

[0511] The following compounds were obtained according to a similarmanner to that of Example 41.

[0512] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(3-methylsulfonyloxypropyl)piperazine

[0513] IR (Neat): 1630, 1470, 1430, 1340, 1270 cm⁻¹

[0514] NMR (CDCl₃, δ): 1.55-5.14 (15H, m), 3.04 (3H, s), 7.00-7.95 (6H,m)

[0515] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(2-methylsulfonyloxypropyl)piperazine

[0516] IR (Neat): 1635, 1430, 1350, 1275, 1170, 1125 cm⁻¹

EXAMPLE 43

[0517] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (250 mg), thiomorpholine (43 mg) and triethylamine (46 mg) indry methanol (5 ml) was refluxed for 2 hours. The reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by column chromatography on silica gel using ethyl acetate asan eluent. The product obtained was dissolved in ethyl acetate andtreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (195 mg).

[0518] [α]_(D) ²³: −23.0° (C=0.5, MeOH)

[0519] IR (Nujol): 3400, 2500, 1640, 1275, 1170, 1130 cm⁻¹

[0520] NMR (CDCl₃, δ): 1.50-5.69 (23H, m), 7.34-7.93 (10H, m)

[0521] MASS: 610 (M+1) (free)

EXAMPLE 44

[0522] The following compounds were obtained according to a similarmanner to that of Example 43.

[0523] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(2-morpholinoethyl) piperazine dihydrocloride

[0524] [α]_(D) ²³: −25.2° (C=0.5, MeOH)

[0525] IR (Nujol): 3400, 2510, 2425, 1635, 1425, 1275, 1170, 1130 cm⁻¹

[0526] NMR (DMSO-d₆, δ): 2.88-5.31 (21H, m), 7.07-8.24 (10H, m)

[0527] MASS: 580 (M+1) (free)

[0528] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(2-thiomorpholinoethyl)piperazine dihydrochloride

[0529] [α]_(D) ²²: −23.7° (C=0.5, MeOH)

[0530] IR (Nujol): 2350, 1640, 1270, 1180 cm⁻¹

[0531] NMR (DMSO-d₆, δ): 2.80-5.31 (21H, m), 7.03-8.20 (10H, m)

[0532] MASS: 596 (M+1) (free)

[0533] (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4-oxopiperidino)propyl]piperazine

[0534] [α]_(D) ²⁴: −19.0° (C=0.5, MeOH)

[0535] IR (Nujol): 3270, 1720, 1625, 1430, 1340, 1275, 1125 cm⁻¹

[0536] NMR (CDCl₃, δ): 1.66-5.20 (23H, m), 6.69-8.28 (8H, m)

[0537] MASS: 595 (M+1)

[0538] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(3-thiomorpholinopropyl) piperazine dihydrochloride

[0539] [α]_(D) ¹⁸: +2.2° (C=0.5, MeOH)

[0540] IR (Nujol): 3400, 2400, 1650, 1280 cm⁻¹

[0541] NMR (DMSO-d₆, δ): 2.10-5.20 (23H, m), 6.92-8.32 (6H, m),11.12-11.72 (2H, m)

[0542] MASS: 628 (M+1) (free)

[0543] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(3-morpholinopropyl)piperazine dihydrochloride

[0544] [α]_(D) ¹⁹: +2.3° (C=0.5, MeOH)

[0545] IR (Nujol): 3400, 2550, 2450, 1650, 1280 cm⁻¹

[0546] NMR (DMSO-d₆, δ): 2.10-5.20 (23H, m), 6.94-8.34 (6H, m),1.08-11.76 (2H, m)

[0547] MASS: 612 (M+1) (free)

[0548] (6)(2R)-4-[3-(4-Acetylpiperidino)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine dihydrochloride

[0549] [α]_(D) ²⁰: −7.2° (C=0.5, MeOH)

[0550] IR (Nujol): 3300, 2600, 1700, 1630, 1275 cm⁻¹

[0551] NMR (DMSO-d₆, δ): 1.67-5.24 (24H, m), 2.16 (3H, s), 6.62-8.28(8H, m), 10.95 (1H, s)

[0552] MASS: 623 (M+1) (free)

[0553] (7) (2R)-4-[3-(Thiazolidin-3-yl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinedihydrochloride

[0554] [α]_(D) ²⁵: −5.4° (C=0.5, MeOH)

[0555] IR (Nujol): 3600-3100, 2700-2250, 1660-1580, 1270, 1120 cm⁻¹

[0556] NMR (DMSO-d₆, δ): 2.20-2.40 (2H, m), 3.00-5.20 (19H, m),6.40-8.25 (8H, m), 10.97 (1H, m), 11.20-11.90 (2H, m)

[0557] MASS: 585 (M+1) (free)

[0558] (8) (2R)-4-[3-(4-Phenyl-1-piperazinyl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinetrihydrochloride

[0559] [α]_(D) ²⁵: −8.0° (C=0.5, MeOH)

[0560] IR (Nujol): 3600-3100, 2750-2300, 1630, 1275, 1120 cm⁻¹

[0561] NMR (DMSO-d₆, δ): 2.05-2.45 (2H, m), 3.05-5.20 (21H, m),6.60-8.05 (13H, m), 10.97 (1H, s), 11.00-11.85 (3H, m)

[0562] MASS: 658 (M+1) (free)

[0563] (9) (2R)-4-[3-(4-cyclohexyl-1-piperazinyl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinetrihydrochloride

[0564] mp: 250° C. (dec.)

[0565] [α]_(D) ²⁵: −7.8° (C=0.5, MeOH)

[0566] IR (Nujol): 3600-3100, 2650-2200, 1640-1600, 1370, 1270, 1120cm⁻¹

[0567] NMR (DMSO-d₆, δ): 1.00-2.40 ( 11H, m), 3.00-5.30 (23H, m),6.60-8.30 (8H, m), 10.97 (1H, s), 11.30-12.30 (3H, m)

[0568] MASS: 664 (M+1) (free)

EXAMPLE 45

[0569] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-methylsulfonyloxyethyl)piperazine (200 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg)in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixturewas concentrated under reduced pressure and the resulting residue waspartitioned between ethyl acetate and aqueous sodium hydrogen carbonatesolution. The organic layer was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography on silica gel using a mixture of ethylacetate and methanol (10:1) as an eluent to afford(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(morpholinoamino)ethyl]piperazine(55 mg).

[0570] [α]_(D) ²²: −16.2° (C=0.5, MeOH)

[0571] IR (Nujol): 3300, 1615, 1275 cm⁻¹

[0572] NMR (DMSO-d₆, δ): 2.14-5.10 (21H, m), 6.0-8.26 (8H, m), 10.91(1h, s)

[0573] MASS: 584 (M+1)

EXAMPLE 46

[0574] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine(100 mg) and 4-phenylpiperidine (60 mg) in acetonitrile (3 ml) wasrefluxed for 2 hours. The reaction mixture was concentrated underreduced pressure and the resulting residue was purified by columnchromatography on silica gel using ethyl acetate-methanol (5:1) as aneluent to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4-phenylpiperidino)propyl]piperazine(90 mg).

[0575] [α]_(D) ²⁰: −24.6° (C=1.0, MeOH)

[0576] IR (Neat): 3250, 1630, 1430, 1275, 1130 cm⁻¹

[0577] NMR (DMSO-d₆, δ): 1.52-4.93 (24H, m), 6.60-8.28 (13H, m), 10.87(1H, s)

[0578] MASS: 657 (M+1)

EXAMPLE 47

[0579] A solution of (2R)-2-(3,4-dichlorobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)piperazine (50 mg) in ethylacetate (3 ml) was treated with 4N hydrogen chloride in ethyl acetatesolution (0.2 ml) and the resulting mixture was concentrated in vacuo togive(2R)-2-(3,4-dichlorobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)piperazine hydrochloride (45 mg) as a powder.

[0580] IR (Neat): 3260, 2550, 1640, 1425, 1275 cm⁻¹

[0581] NMR (DMSO-d₆, δ): 2.80-5.53 (13H, m), 6.91-8.32 (6H, m), 10.96(1H, br s)

[0582] MASS: 530 (M+1) (free)

EXAMPLE 48

[0583] The following compounds were obtained according to a similarmanner to that of Example 47.

[0584] (1) (2R)-4-(4-Aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride

[0585] mp: 179° C. (dec.)

[0586] [α]_(D) ²⁵: −16.6° (C=0.5, MeOH)

[0587] IR (Nujol): 3400-3050, 2650-2300, 1660-1580, 1275, 1125 cm⁻¹

[0588] NMR (DMSO-d₆, δ): 2.00-2.20 (6H, m), 2.80-5.05 (11H, m),6.45-8.25 (10H, m), 11.40-11.90 (2H, m)

[0589] MASS: 555 (M+1) (free)

[0590] (2) (2R)-4-(4-Nitrobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride

[0591] mp: 140° C. (dec.)

[0592] [α]_(D) ²⁵: −18.4° (C=0.5, MeOH)

[0593] IR (Nujol): 3600-3200, 2650-2200, 1640, 1520, 1350, 1275, 1130cm⁻¹

[0594] NMR (DMSO-d₆, δ): 2.00-2.20 (6H, m), 2.80-5.00 (11H, m),6.50-8.40 (10H, m)

[0595] MASS: 580 (M+1) (free)

EXAMPLE 49

[0596] To a solution of (2R)-4-[4,4-ethylenedioxy-4-(4-fluorophenyl)butyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine(210 mg) in ethyl acetate was added 4N hydrogen chloride in ethylacetate solution (0.5 ml) and the whole was stirred at room temperaturefor 23 hours. The solution was evaporated in vacuo. The residue wastriturated with a mixture of ethyl acetate and diisopropyl ether to give(2R)-4-[4-florophenyl)-4-oxobutyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazinehydrochloride (183.7 mg).

[0597] mp: 161° C. (dec.)

[0598] [α]_(D) ²⁵: −14.2° (C=0.5, MeOH)

[0599] IR (Nujol): 3400-3150, 2650-2300, 1675, 1635, 1595, 1280-1250,1275, 1125 cm⁻¹

[0600] NMR (DMSO-d₆, δ): 2.00-2.25 (2H, m), 3.05-5.20 (13H, m),6.55-8.25 (12H, m), 10.95 (1H, s), 11.10-11.50 (1H, m)

[0601] MASS: 620 (M+1) (free)

Preparation 6

[0602] Tetrahydrofuran (15 ml) was added to 70% solution of sodiumbis(2-methoxyethoxy)aluminum hydride in toluene (49.7 g) under anatmosphere of nitrogen and then cooled. A solution of4-morpholino-2-butyn-1-ol (3.0 g) in tetrahydrofuran (15 ml) was addeddropwise maintaining the reaction temperature 4-5° C. After beingstirred for 10 minutes, the reaction mixture was allowed to warm to roomtemperature. After 1 hour, water (6 ml) and 10% aqueous sodium hydroxidesolution (4.5 ml) were added cautiously and then filtered. The filtratewas dried over potassium carbonate and concentrated under reducedpressure to give an oily product, which was purified by columnchromatography on silica gel using ethyl acetate-methanol (5:1) toafford (E)-4-morpholino-2-buten-1-ol (1.08 g).

[0603] IR (Neat): 3350, 1450, 1110, 990, 855 cm⁻¹

[0604] NMR (CDCl₃, δ): 2.48 (4H, t, J=4.7Hz), 2.77 (1H, s), 3.02 (2H, d,J=5.4Hz), 3.73 (4H, t, J=4.7Hz), 4.15 (2H, d, J=4.0Hz), 5.64-5.96 (2H,m)

[0605] MASS: 158 (M+1)

Preparation 7

[0606] Thionyl chloride (0.96 ml) was added dropwise to a solution of(E)-4-morpholino-2-buten-1-ol (1.03 g) in dichloromethane (10 ml) atice-bath temperature. After 3 hours, the reaction mixture was evaporatedunder reduced pressure and the resulting residue was triturated withethyl acetate to give (E)-4-morpholino-2-butenyl chloride hydrochloride(0.98 g).

[0607] mp: 155-160° C.

[0608] IR (Nujol): 2750-2700, 1275, 1255, 1120, 1078, 1065, 975 cm⁻¹

[0609] NMR (DMSO-d₆, δ): 2.80-3.55 (4H, m), 3.64-4.10 (6H, m), 4.26 (2H,d, J=5.7Hz), 5.90-6.25 (2H, m), 11.82 (1H, br s)

[0610] MASS: 176 (M) (free)

EXAMPLE 50

[0611] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.20 g), 5-morpholino-3-pentynyl chloride hydrochloride(0.175 g), potassium carbonate (0.303 g) and potassium iodide (10 mg) indry acetonitrile (4 ml) was stirred under reflux for 60 hours. Afterremoval of the solvent, the resulting residue was dissolved with ethylacetate. The solution was washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using toluene-ethyl acetate (1:2)as eluent and treated with 4N hydrogen chloride in ethyl acetatesolution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(5-morpholino-3-pentynyl)piperazine dihydrochloride (0.174 g).

[0612] [α]_(D) ²¹: −19.5° (C=0.5, MeOH)

[0613] IR (Nujol): 3600-3150, 2700-2300, 1640, 1280, 1170, 1185 cm⁻¹

[0614] NMR (DMSO-d₆, δ): 2.90-5.20 (23H, m), 6.80-8.30 (8H, m), 10.95(1H, s), 11.79 (2H, br s)

[0615] MASS: (APCI): 608 (M+2), 607 (M+1) (free)

[0616] Anal. Calcd. for C₃₁H₃₂F₆N₄O₂HCl1.5H₂O:

[0617] C 52.70, H 5.28, N 7.93

[0618] Found: C 52.72, H 5.54, N 7.60

EXAMPLE 51

[0619] To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.2 g),1-methyl-4-formyl-1H-pyrazole (50 mg), and sodium triacetoxyborohydride(151 mg) in dichloromethane (2 ml) was added one drop of acetic acid.After being stirred at room temperature overnight, the solution wasevaporated under reduced pressure. The resulting residue was partitionedbetween ethyl acetate and aqueous sodium hydrogen carbonate solution.The organic layer was separated, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using ethyl acetate-methanol as eluent andtreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride (97 mg).

[0620] mp: 243-244° C.

[0621] [α]_(D) ^(18.2): −16.8° (C=0.3, MeOH)

[0622] IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1165, 1130 cm⁻¹

[0623] NMR (DMSO-d₆, δ): 1.97-2:28 (7H, m), 2.78-5.10 (13H, m),6.50-8.30 (8H, m), 11.24-11.74 (1H, br m)

[0624] MASS (APCI): 539 (M+1) (free)

[0625] Anal. Calcd. for C₂₇H₂₈F₆N₄O·HCl·2.7H₂O:

[0626] C 52.00, H 5.56, N 8.98

[0627] Found: C 51.82, H 5.15, N 8.99

EXAMPLE 52

[0628] The following compounds were obtained according to a similarmanner to that of Example 51.

[0629] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(1-methyl-1H-imidazol-4-yl)methyl]piperazinedihydrochloride

[0630] [α]_(D) ²⁶: −11.80° (C=0.5, MeOH)

[0631] IR (Neat): 3350, 2550, 1640, 1430, 1275, 1170, 1130 cm⁻¹

[0632] NMR (DMSO-d₆, δ): 2.07 (3H, s), 2.17 (3H, s), 2.72-5.10 (11H, m),3.88 (3H, s), 6.60-9.08 (8H, m)

[0633] MASS: 539 (M+1) (free)

[0634] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(1-methyl-1H-imidazol-2-yl)methyl]piperazinedihydrochloride

[0635] [α]_(D) ²⁵: −12.10° (C=0.5, MeOH)

[0636] IR (Neat): 3350, 2500, 1640, 1430, 1280, 1175, 1130 cm⁻¹

[0637] NMR (DMSO-d₆, δ): 2.07 (3H, s), 2.16 (3H, s), 2.53-5.14 (11H, m),3.94 (3H, s), 6.47-8.26 (8H, m)

[0638] MASS: 539 (M+1) (free)

EXAMPLE 53

[0639] The following compounds were obtained according to a similarmanner to that of Example 43.

[0640] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(3-morpholinopropyl)piperazine dihydrochloride

[0641] mp: 220-230° C.

[0642] [α]_(D) ^(21.5): −17.3° (C=0.3, MeOH)

[0643] IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm⁻¹

[0644] NMR (DMSO-d₆, δ) 1.92-5.22 (29H, m), 8.56-8.28 (6H, m), 11.43(2H, br s)

[0645] MASS (APCI): 572 (M+1) (free)

[0646] Anal. Calcd. for C₂₉H₃₅F₆N₃O₂·2HCl:

[0647] C 54.04, H 5.79, N 6.52

[0648] Found: C 53.72, H 5.80, N 6.29

[0649] (2) (2R)-4-[2-[N,N-Bis(2-methoxyethyl)amino]ethyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazinedihydrochloride

[0650] [α]_(D) ²²: −9.6° (C=0.5, MeOH)

[0651] IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm⁻¹

[0652] NMR (DMSO-d₆, δ): 1.92-5.22 (27H, m), 3.32 (6H, s), 6.56-8.28(6H, m)

[0653] MASS (APCI): 604 (M+1) (free)

[0654] Anal. Caicd. for C₃₀H₃₉F₆N₃O₃·2HCl·1.6H₂O:

[0655] C 51.08, H 6.32, N 5.96

[0656] Found: C 51.06, H 6.40, N 6.14

[0657] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(1,2,3,6-tetrahydropyridin-1-yl)propyl]piperazinedihydrochloride

[0658] mp: >200° C.

[0659] [α]_(D) ²³: −2.30° (C=0.5, MeOH)

[0660] IR (Nujol): 3500-3100, 2700-2400, 1630 cm⁻¹

[0661] NMR (DMSO-d₆, δ): 2.20-4.20 (21H, m), 5.72 (1H, d, J=10.2Hz),5.93 (1H, d, J=10.2Hz), 6.55-8.23 (8H, m), 10.95 (1H, br s)

[0662] MASS (APCI): 579 (M+1) (free)

[0663] Anal. Calcd. for C₃₀H₃₂F₆N₄O·2HCl·2H₂O:

[0664] C 52.41, H 5.57, N 8.15

[0665] Found: C 52.03, H 5.77, N 7.72

[0666] (4) (2R)-4-[3-(3-Azabicyclo[3.2.2]non-3-yl)propyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl) piperazinedihydrochloride

[0667] mp: 150° C. (dec.)

[0668] [α]_(D) ^(19.1): −2.90° (C=0.5, MeOH)

[0669] IR (Nujol): 3500-3100, 2700-2400, 1630 cm⁻¹

[0670] NMR (DMSO-d₆, δ): 1.60-3.90 (29H, m), 6.90-8.30 (6H, m)

[0671] MASS (APCI): 652 (M+2), 650 (M+1) (free)

[0672] Anal. Calcd. for C₃₁H₃₅Cl₂F₆N₃O·2HCl·H₂O:

[0673] C 50.22, H 5.30, N 5.67

[0674] Found: C 50.25, H 5.60, N 5.32

[0675] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-[3-(4,1′-bipiperidin-1-yl)propyl]piperazinetrihydrochloride

[0676] mp: >200° C.

[0677] [α]_(D) ^(28.4): −3.40° (C=0.5, MeOH)

[0678] IR (Nujol): 3300, 2700-2400, 1630, 1450 cm⁻¹

[0679] NMR (DMSO-d₆, δ): 1.60-3.90 (34H, m), 6.90-8.30 (6H, m)

[0680] MASS (FAB): 693 (M+1), 695 (free)

[0681] Anal. Calcd. for C₃₃H₄₀Cl₂F₆N₄O·3HCl:

[0682] C 49.36, H 5.40, N 6.98

[0683] Found: C 49.81, H 5.75, N 6.75

EXAMPLE 54

[0684] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-morpholino-2-butynyl)piperazine (141 mg) in methanol (10 ml) was hydrogenated over 10% Pd-C(50 mg) at room temperature under 2-3 atoms. After removal of thecatalyst by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel using dichloromethane-methanol as eluent and treated with 4Nhydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-morpholinobutyl) piperazinedihydrochloride (106 mg).

[0685] mp: 279° C.

[0686] [α]_(D) ²³: −13.5° (C=0.5, MeOH)

[0687] IR (Nujol): 3300, 2700-2400, 1645, 1500, 1445, 1370, 2970, 1170cm⁻¹

[0688] NMR (DMSO-d₆, δ): 1.70-5.22 (31H, m), 6.56-8.28 (6H, m),11.00-11.40 (2H, m)

[0689] MASS (APCI): 586 (M+1) (free)

EXAMPLE 55

[0690] The following compound was obtained according to a similar mannerto that of Example 54.

[0691](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(5-morpholinopentyl)piperazine dihydrochloride

[0692] [α]_(D) ²¹: −6.10° (C=0.5, MeOH)

[0693] IR (Neat): 3400-3200, 2700-2400, 1640, 1430 cm⁻¹

[0694] NMR (DMSO-d₆, δ): 1.50-5.20 (27H, m), 6.60-8.30 (8H, m),10.80-11.50 (3H, m)

[0695] MASS: 611 (M+1) (free)

[0696] Anal. Calcd. for C₃₁H₃₆F₆N₄O₂·2HCl·1.3H₂O:

[0697] C 52.67, H 5.79, N 7.92

[0698] Found: C 52.66, H 6.13, N 7.76

EXAMPLE 56

[0699] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(5-morpholino-3-pentynyl)piperazine (200 mg) was treated with 4N hydrogen chloride in ethylacetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(5-morpholino-3-pentynyl) piperazinedihydrochloride.

[0700] [α]_(D) ²¹: −25.2° (C=0.5,MeOH)

[0701] IR (Neat): 3700-3100, 2920, 2750-2250, 1635, 1500, 1430, 1275,1170, 1120 cm⁻¹

[0702] NMR (DMSO-d₆, δ): 2.05-2.20 (6H, m), 2.75-5.15 (23H, m),6.65-8.28 (6H, m), 11.60-12.20 (2H, m)

[0703] MASS: 596 (M+1) (free)

[0704] Anal. Calcd. for C₃₁H₃₅F₆N₃O₂HCl·1.5H₂O:

[0705] C 53.53, H 5.80, N 6.04

[0706] Found: C 53.47, H 6.14, N 5.91

EXAMPLE 57

[0707] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine fumarate (9.13 g) was treated with aqueous 10% sodiumhydroxide solution (65 ml) and dichloromethane (65 ml). The organiclayer was separated, washed with brine, dried over magnesium sulfate andevaporated under reduced pressure. A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine obtained bythe above procedure, potassium carbonate (3.60 g) and1,4-dichloro-2-butyne (1.9 ml) in N,N-dimethylformamide (72 ml ) wasstirred for 4.5 hours at room temperature. The mixture was poured intowater (360 ml) and extracted with ethyl acetate. The extract was washedwith brine, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using toluene-ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)piperazine (4.86 g).

[0708] IR (Neat): 1706, 1635, 1503, 1275, 1125 cm⁻¹

[0709] NMR (CDCl₃, δ): 2.05-5.20 (19H, m), 6.60-7.84 (6H, m)

[0710] MASS (APCI): 531 (M+1)

EXAMPLE 58

[0711] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)piperazine (0.49 g), 3-methylmorpholine hydrochloride (0.15 g),potassium carbonate (0.39 g) and potassium iodide (10 mg) in dryN,N-dimethylformamide (5 ml) was stirred for 5 hours at roomtemperature. The mixture was poured into water and extracted with ethylacetate. The extract was washed with brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using ethyl acetate as eluent andtreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3-methylmorpholino)-2-butynyl]piperazine dihydrochloride (0.28 g).

[0712] mp: 150-160° C.

[0713] [α]_(D) ^(28.4): −5.71° (C=1.0, MeOH)

[0714] IR (Nujol): 3300, 2700-2400, 1650, 1430 cm⁻¹

[0715] NMR (DMSO-d₆, δ): 1.20-5.22 (29H, m), 6.60-8.20 (6H, m),12.20-12.40 (2H, m)

[0716] MASS (APCI): 596 (M+1) (free)

[0717] Anal. Calcd. for C₃₁H₃₅F₆N₃O₂·2HCl·1.7H₂O:

[0718] C 53.25, H 5.82, N 6.01

[0719] Found: C 53.28, H 5.97, N 5.80

EXAMPLE 59

[0720] The following compounds were obtained according to a similarmanner to that of Example 58.

[0721] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(2-methoxymethylmorpholino)-2-butynyl]piperazinedihydrochloride

[0722] mp: 150-165° C.

[0723] [α]_(D) ^(28.4): −8.86° (C=0.7, MeOH)

[0724] IR (Nujol): 3300, 2700-2400, 1640, 1430 cm⁻¹

[0725] NMR (DMSO-d₆, δ): 2.00-5.22 (28H, m), 3.25 (3H, s), 6.50-8.20(6H, m), 12.20-12.40 (2H, m)

[0726] MASS (APCI): 626 (M+1) (free)

[0727] Anal. Calcd. for C₃₂H₃₇F₆N₃O₃·2HCl·H₂O:

[0728] C 53.64, H 5.77, N 5.86

[0729] Found: C 53.60, H 5.94, N 5.67

[0730] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(2-fluoromethylmorpholino)-2-butynyl]piperazinedihydrochloride

[0731] mp: 175-180° C.

[0732] [α]_(D) ^(28.4): −8.75° (C=0.7, MeOH)

[0733] IR (Nujol): 3300, 2700-2400, 1635, 1500 cm⁻¹

[0734] NMR (DMSO-d₆, δ): 2.00-5.22 (28H, m), 6.50-8.20 (6H, m)

[0735] MASS (APCI): 614 (M+1) (free)

[0736] Anal. Calcd. for C₃₁H₃₄F₇N₃O₂·2HCl·H₂O:

[0737] C 52.85, H 5.44, N 5.96

[0738] Found: C 52.82, H 5.45, N 5.74

[0739] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazinedihydrochloride

[0740] mp: 180-190° C.

[0741] [α]_(D) ^(28.3): −7.24° (C=1.05, MeOH)

[0742] IR (Nujol): 3300, 2700-2400, 1635 cm⁻¹

[0743] NMR (DMSO-d₆, δ): 1.30-1.40 (6H, m), 2.00-5.22 (25H, m),6.60-8.20 (6H, m), 12.05-12.20 (2H, m)

[0744] MASS (APCI): 610 (M+1H) (free)

[0745] Anal Calcd. for C₃₂H₃₇F₆N₃O₂·2HCl·2.5H₂O:

[0746] C 52.82, H 6.09, N 5.68

[0747] Found: C 52.84, H 5.89, N 5.78

[0748] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((2S)-2-methoxymethylpyrrolidino)-2-butynyl]piperazinedihydrochloride

[0749] mp: 195-197° C.

[0750] [α]_(D) ^(28.4): −19.79° (C=0.7, MeOH)

[0751] IR (Nujol): 3450, 2700-2400, 1640, 1450 cm⁻¹

[0752] NMR (DMSO-d₆, δ): 2.00-5.22 (28H, m), 3.32 (3H, s), 6.50-8.20(6H, m), 11.50-11.70 (2H, m)

[0753] MASS (APCI): 610 (M+1) (free)

[0754] Anal. Calcd. for C₃₂H₃₇F₆N₃O₂·2HCl·2H₂O:

[0755] C 53.49, H 6.03, N 5.85

[0756] Found: C 53.66, H 5.73, N 5.82

[0757] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3-methoxymethylmorpholino)-2-butynyl]piperazinedihydrochloride

[0758] mp: 140-155° C.

[0759] [α]_(D) ^(28.4): −7.22° (C=0.63, MeOH)

[0760] IR (Nujol): 3300, 2700-2400, 1635, 1440 cm⁻¹

[0761] NMR (DMSO-d₆, δ): 2.00-5.22 (28H, m), 3.32 (3H, s), 6.50-8.20(6H, m)

[0762] MASS (APCI): 626 (M+1) (free)

[0763] Anal. Calcd. for C₃₂H₃₇F₆N₃O₃·2HCl:

[0764] C 52.32, H 5.90, N 5.72

[0765] Found: C 52.35, H 6.11, N 5.43

EXAMPLE 60

[0766] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.38 g), potassium carbonate (0.42 g),3-(3-pyridyl)-2-propynyl chloride hydrochloride (1.9 ml) and smallamount of potassium iodide in N,N-dimethylformamide (10 ml) was stirredfor 2 hours at 40° C. The mixture was poured into water and extractedwith ethyl acetate. The extract was washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel using ethyl acetate aseluent and treated with 4N hydrogen chloride in ethyl acetate solutionto give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3-pyridyl)-2-propynyl]piperazinedihydrochloride (0.26 g).

[0767] mp: 140-150° C.

[0768] [α]_(D) ^(28.4): −10.13° (C=0.8, MeOH)

[0769] IR (Nujol): 3300, 2700-2400, 1630, 1450 cm⁻¹

[0770] NMR (DMSO-d₆, δ): 2.00-5.22 (17H, m), 6.50-8.20 (8H, m),8.70-8.85 (2H, m)

[0771] MASS (APCI): 560 (M+1) (free)

[0772] Anal. Calcd. for C₃₀H₂₇F₆N₃O·2HCl·2.8H₂O:

[0773] C 52.76, H 5.11, N 6.15

[0774] Found: C 52.74, H 4.96, N 6.05

EXAMPLE 61

[0775] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chloro-2-butenyl]-2-(2-naphthylmethyl)piperazine(300 mg), thiomorpholine (0.054 ml) and powdered potassium carbonate(100 mg) in dry acetonitrile (3 ml) was heated at 50° C. for 10 hours.Additional potassium carbonate (100 mg) and thiomorpholine (0.054 ml)were added and then the resulting mixture was further heated at the sametemperature. After 2 hours, the reaction mixture was cooled and thenfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by column chromatography on silica gelusing a mixture of dichloromethane and methanol (40:1). The obtainedproduct was dissolved in ethyl acetate and treated with 4N hydrogenchloride in ethyl acetate (0.6 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-((E)-4-thiomorpholino-2-butenyl)piperazine dihydrochloride (190 mg).

[0776] mp: >230° C.

[0777] [α]_(D) ^(28.9): −14.50° (C=0.5, MeOH)

[0778] IR (Nujol): 3650-3100, 2410, 1640, 1274, 1130 cm⁻¹

[0779] NMR (DMSO-d₆, δ): 2.55-5.30 (21H, m), 6.00-6.30 (2H, m),7.00-8.20 (10H)

[0780] MASS: 622 (M+1) (free)

EXAMPLE 62

[0781] The following compounds were obtained according to a similarmanner to that of Example 61.

[0782] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(E)-4-morpholino-2-butenyl]piperazinedihydrochloride

[0783] mp: >230° C.

[0784] [α]_(D) ^(28.7): −16.60° (C=0.5, MeOH)

[0785] IR (Nujol): 3600-3100, 2450, 1639, 1273, 1130 cm⁻¹

[0786] NMR (DMSO-d₆, δ): 2.80-5.30 (21H, m) 6.10-6.30 (2H, m), 7.00-8.25(10H, m)

[0787] MASS: 606 (M+1) (free)

[0788] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-thiomorpholino-2-butenyl]piperazinedihydrochloride

[0789] mp: >230° C.

[0790] [α]_(D) ^(25.8): 5.20° (C=0.25, DMSO)

[0791] IR (Nujol): 3600-3100, 2450, 1642, 1274, 1130 cm⁻¹

[0792] NMR (DMSO-d₆, δ): 2.10-5.10 (27H, m), 5.90-6.30 (2H, m),6.65-7.05 (3H, m), 7.57 (2H, s), 8.05 (1H, s)

[0793] MASS: 600 (M+1) (free)

EXAMPLE 63

[0794] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chloro-2-butenyl]-2-(3,4-dimethylbenzyl)piperazine(450 mg), 3,3-dimethylmorpholine hydrochloride (130 mg) and powderedpotassium carbonate (350 mg) in dry acetonitrile (5 ml) was heated atreflux temperature for 3 hours. Additional potassium carbonate (350 mg)and 3,3-dimethylmorpholine hydrochloride (130 mg) were added and thenthe resulting mixture was further heated at reflux temperature. After 6hours, the reaction mixture was cooled and then filtered. The filtratewas concentrated under reduced pressure and the resulting residue waspurified by column chromatography on silica gel using a mixture ofdichloromethane and methanol (50:1). The obtained product was dissolvedin ethyl acetate and treated with 4N hydrogen chloride in ethyl acetatesolution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-(3,3-dimethylmorpholino)-2-butenyl]piperazinedihydrochloride (370 mg).

[0795] mp: >230° C.

[0796] [α]_(D) ^(25.5): −11.70° (C=0.5, MeOH)

[0797] IR (Nujol): 3400, 2450, 1639, 1274, 1130 cm⁻¹

[0798] NMR (DMSO-d₆, δ): 1.34-1.40 (6H, m), 2.10-2.18 (6H, m), 2.70-5.20(19H, m), 6.10-6.30 (2H, m), 6.65-8.30 (6H, m), 11.20-12.00 (2H, m)

[0799] MASS: 612 (M+1) (free)

EXAMPLE 64

[0800] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (1.0 g), (E)-1,4-dichloro-2-butene (0.31 ml) and powderedpotassium carbonate (0.4 g) in dry acetonitrile (10 ml) was heated at50° C. After 4 hours, the reaction mixture was cooled and then filtered.The filtrate was concentrated under reduced pressure and the resultingresidue was purified by column chromatography on silica gel using amixture of toluene and ethyl acetate (4:1) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-chloro-2-butenyl]piperazine(0.53 g) as an oil.

[0801] IR (Neat): 3460, 1638, 1272, 1125, 900 cm⁻¹

[0802] NMR (CDCl₃, δ): 2.00-5.20 (19H, m), 5.75-6.00 (2H, m), 6.60-8.00(6H, m)

[0803] MASS: 533 (M+1)

EXAMPLE 65

[0804] The following compound was obtained according to a similar mannerto that of Example 64.

[0805](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(E)-4-chloro-2-butenyl]piperazine

[0806] IR (Neat): 1637, 1273, 1128, 900 cm⁻¹

[0807] NMR (CDCl₃, δ): 2.05-5.20 (13H, m), 5.80-6.00 (2H, m), 7.10-8.10(10H, m)

[0808] MASS: 555 (M+1)

EXAMPLE 66

[0809] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg)in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixturewas concentrated under reduced pressure and the resulting residue waspartitioned between ethyl acetate and aqueous sodium hydrogen carbonatesolution. The organic layer was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography on silica gel using a mixture of ethylacetate and methanol (10:1) to afford an oily product, which was treatedwith 4N hydrogen chloride in ethyl acetate solution (0.5 ml) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(morpholinoamino)propyl]piperazine dihydrochloride (58 mg).

[0810] [α]_(D) ²³: −3.60° (C=0.5, MeOH)

[0811] IR (Nujol): 3300, 2500, 1630, 1420, 1275 cm⁻¹

[0812] NMR (DMSO-d₆, δ): 2.00-5.24 (23H, m), 6.60-8.28 (8H, m), 10.94(1H, s), 11.50 (1H, br s)

[0813] MASS: 598 (M+1) (free)

EXAMPLE 67

[0814] The following compounds were obtained according to a similarmanner to that of Example 66.

[0815] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[2-(cis-2,6-dimethylmorpholino)ethyl]piperazinedihydrochloride

[0816] [α]_(D) ²⁰: −2.60° (C=0.5, MeOH)

[0817] IR (Nujol): 3350, 2600, 1640, 1280, 1175, 1130 cm⁻¹

[0818] NMR (DMSO-d₆, δ): 1.55 (6H, m), 2.52-5.20 (19H, m), 6.60-8.24(8H, m), 10.95 (1H, s)

[0819] MASS: 597 (M+1) (free)

[0820] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(cis-2,6-dimethylmorpholino)propyl]piperazinedihydrochloride

[0821] [α]_(D) ²⁰: −5.30° (C=0.5, MeOH)

[0822] IR (Nujol): 3350, 2600, 1640, 1280 cm⁻¹

[0823] NMR (DMSO-d₆, δ): 1.20 (6H, m), 2.08-5.20 (21H, m), 6.63-8.33(8H, m), 10.94 (1H, s)

[0824] MASS: 611 (M+1) (free)

[0825] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(1-imidazolyl)ethyl]piperazinedihydrochloride

[0826] [α]_(D) ²¹: −16.20° (C=0.5, MeOH)

[0827] IR (Nujol): 3350, 2700, 2575, 1640, 1430, 1280, 1170, 1130 cm⁻¹

[0828] NMR (DMSO-d₆, δ) : 2.04-5.20 (13H, m), 2.09 (3H, s), 2.18 (3H,s), 6.55-8.22 (8H, m), 9.29 (1H, s)

[0829] MASS: 539 (M+1) (free)

[0830] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(morpholinoamino)propyl]piperazine dihydrochloride

[0831] [α]_(D) ²⁰: −14.10° (C=0.5, MeOH)

[0832] IR (Nujol): 3350, 2550, 1640, 1430, 1280 cm⁻¹

[0833] NMR (DMSO-d₆, δ): 1.97-5.14 (23H, m), 2.10 (3H, s), 2.18 (3H, s),6.64-8.24 (6H, m), 10.92 (1H, br s)

[0834] MASS: 587 (M+1) (free)

[0835] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(3-pyridylmethylamino)ethyl]piperazinetrihydrochloride

[0836] [α]_(D) ²¹: 3.50° (C=0.5, MeOH)

[0837] IR (Nujol): 3400, 2600, 1640, 1430, 1280, 1170, 1130 cm⁻¹

[0838] NMR (DMSO-d₆, δ): 2.07-5.20 (13H, m), 2.10 (3H, s), 2.18 (3H, s),4.50 (2H, s), 6.60-9.09 (10H, m), 10.32 (1H, br s)

[0839] MASS: 679 (M+1) (free)

[0840] (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-homomorpholinoethyl)piperazine dihydrochloride

[0841] [α]_(D) ¹⁷: −9.90° (C=0.5, MeOH)

[0842] IR (Nujol): 3400, 2600, 2450, 1640, 1430, 1280 cm⁻¹

[0843] NMR (DMSO-d₆, δ): 2.04-5.17 (23H, m), 2.10 (3H, s), 2.18 (3H, s),6.62-8.26 (6H, m)

[0844] MASS: 572 (M+1) (free)

[0845] (7)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(3-homomorpholinopropyl)piperazine dihydrochloride

[0846] [α]_(D) ¹⁹: −10.0° (C=0.5, MeOH)

[0847] IR (Nujol): 3400, 2600, 1635, 1430, 1280 cm⁻¹

[0848] NMR (DMSO-d₆, δ): 1.73-5.20 (25H, m), 2.10 (3H, s), 2.18 (3H, s),6.62-8.24 (6H, m)

[0849] MASS: 586 (M+1) (free)

[0850] (8)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-homomorpholinopropyl)piperazine dihydrochloride

[0851] [α]_(D) ¹⁷: −5.50° (C=0.5, MeOH)

[0852] IR (Nujol): 3300, 2650, 1640, 1275 cm⁻¹

[0853] NMR (DMSO-d₆, δ): 1.90-5.23 (25H, m), 6.62-8.34 (8H, m), 10.95(1H, s)

[0854] MASS: 597 (M+1) (free)

[0855] (9)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-[3-(4-acetylpiperidino)propyl]piperazinedihydrochloride

[0856] [α]_(D) ²⁰: 2.20° (C=0.5, MeOH)

[0857] IR (Nujol): 3350, 2650, 1700, 1630, 1275 cm⁻¹

[0858] NMR (DMSO-d₆, δ): 1.69-5.21 (24H, m), 2.16 (3H, s), 6.97-8.36(6H, m)

[0859] MASS: 652 (M) (free)

[0860] (10)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(4-acetylpiperidino)propyl]piperazinedihydrochloride

[0861] [α]_(D) ²⁰: −11.30° (C=0.5, MeOH)

[0862] IR (Nujol): 3425, 3375, 2500, 1705, 1640, 1275 cm⁻¹

[0863] NMR (DMSO-d₆, δ): 1.67-5.20 (24H, m), 2.16 (6H, s), 2.18 (3H, s),6.62-8.25 (6H, m), 10.60 (1H, br s), 11.49 (1H, br s)

[0864] MASS: 612 (M+1) (free)

[0865] (11)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(2-morpholinoethyl)piperazine dihydrochloride

[0866] [α]_(D) ²⁰: 6.10° (C=0.5, MeOH)

[0867] IR (Nujol): 3350, 2600, 1630, 1270 cm⁻¹

[0868] NMR (DMSO-d₆, δ): 2.14-5.16 (21H, m), 6.93-8.27 (6H, m)

[0869] MASS: 598 (M) (free)

[0870] (12)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4-methoxypiperidino)propyl]piperazinedihydrochloride

[0871] [α]_(D) ¹⁹: −6.70° (C=0.5, MeOH)

[0872] IR (Nujol): 3300, 2550, 1625, 1270 cm⁻¹

[0873] NMR (DMSO-d₆, δ): 1.57-5.20 (24H, m), 3.27 (3H, s), 6.60-8.28(8H, m), 10.95 (1H, s)

[0874] MASS: 611 (M+1) (free)

[0875] (13)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-[N-(2-methoxyethyl) -N-methylamino ]ethyl]piperazine dihydrochloride

[0876] mp: 222° C. (dec.)

[0877] [α]_(D) ²³: −12.50° (C=0.5, MeOH)

[0878] IR (Nujol): 3380, 2400, 1644, 1275, 1130 cm⁻¹

[0879] NMR (DMSO-d₆, δ): 2.0-2.3 (7H, m) , 2.88 (3H, s), 3.33 (3H, s),2.3-5.3 (18H, m), 6.6-8.3 (6H, m)

[0880] MASS: 560 (M+1) (free)

[0881] (14)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(hexamethyleneimino)propyl]piperazinedihydrochloride

[0882] [α]_(D) ²⁶: −11.70° (C=0.5, MeOH)

[0883] IR (Neat): 3400, 2600, 1640, 1430, 1280 cm⁻¹

[0884] NMR (DMSO-d₆, δ): 1.49-5.20 (27H, m), 2.10 (3H, s), 2.19 (3H, s),6.67-8.23 (6H, m)

[0885] MASS: 584 (M+1) (free)

[0886] (15)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(4-pyridylmethylamino)ethyl]piperazinetrihydrochloride

[0887] [α]_(D) ²⁵: −0.20° (C=0.5, MeOH)

[0888] IR (Neat): 3400, 2600, 1640, 1430, 1280, 1175, 1130 cm⁻¹

[0889] NMR (DMSO-d₆, δ): 2.10 (3H, s), 2.18 (3H, s), 2.64-5.20 (13H, m),4.16 (2H, s), 6.40-8.97 (10H, m)

[0890] MASS: 579 (M+1) (free)

[0891] (16)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(1,2,4-triazol-3-ylamino)propyl]piperazine dihydrochloride

[0892] [α]_(D) ²⁴: −10.50° (C=0.5, MeOH)

[0893] IR (Neat): 3075, 2700, 1675, 1640, 1430, 1280, 1170, 1130 cm⁻¹

[0894] NMR (DMSO-d₆, δ): 2.05-5.20 (15H, m), 2.09 (3H, s), 2.18 (3H, s),6.60-8.34 (9H, m)

[0895] MASS: 569 (M+1) (free)

EXAMPLE 68

[0896] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl) piperazine(300 mg), 4-thiomorpholino-2-butynyl chloride hydrochloride (170 mg) andpowdered potassium carbonate (210 mg) in dry acetonitrile (3 ml) wasrefluxed for 7.5 hours in the presence of potassium iodide (20 mg). Thereaction mixture was cooled and then filtered. The filtrate wasconcentrated under reduced pressure and the resulting residue waspurified by column chromatography on silica gel using a mixture of ethylacetate and methanol (50:1). The obtained product was dissolved in ethylacetate and treated with 4N hydrogen chloride in ethyl acetate solution(0.6 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(4-thiomorpholino-2-butynyl) piperazinedihydrochloride (300 mg).

[0897] mp: 152-156° C.

[0898] [α]_(D) ²⁷: −47.30° (C=0.5, MeOH)

[0899] IR (Nujol): 3350, 2500, 1637, 1275, 1125 cm⁻¹

[0900] NMR (DMSO-d₆, δ): 2.70-5.30 (21H, m), 7.00-8.20 (10H, m)

[0901] MASS: 620 (M+1) (free)

EXAMPLE 69

[0902] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)piperazine (200 mg), 1-cyclohexylpiperazine (63 mg) and powderedpotassium carbonate (210 mg) in dry N,N-dimethylformamide (2 ml) wasstirred for 12 hours at room temperature. Additional1-cyclohexylpiperazine (25 mg) was added and after 2 hours the reactionmixture was poured into water (20 ml) and extracted with ethyl acetate.The organic layer was washed with brine and dried over magnesiumsulfate. After evaporation of the solvent, the resulting residue waspurified by column chromatography on silica gel using a mixture ofdichloromethane and methanol (30:1). The obtained product was dissolvedin ethyl acetate and treated with 4N hydrogen chloride in ethyl acetatesolution (0.6 ml) to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(4-cyclohexylpiperazin-1-yl)-2-butynyl]piperazinetrihydrochloride (220 mg).

[0903] mp: 175-190° C.

[0904] [α]_(D) ^(25.2): −7.20° (C=0.5, MeOH)

[0905] IR (Nujol): 3370, 2750-1920, 1635, 1276, 1126 cm⁻¹

[0906] NMR (DMSO-d₆, δ): 1.02-5.20 (38H, m), 6.60-8.30 (6H, m)

[0907] MASS: 664 (M+1) (free)

EXAMPLE 70

[0908] Potassium carbonate (187 mg) and 2-(chloromethyl) pyridinehydrochloride (81 mg) were added to a solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (200 mg) in N,N-dimethylformamide (4 ml) at room temperaturewith stirring. After 2 hours, the reaction mixture was poured into water(50 ml) and extracted with ethyl acetate. The organic layer was washedwith water and then dried over magnesium sulfate, and evaporated underreduced pressure. The obtained residue was purified by columnchromatography on silica gel using a mixture of ethyl acetate andtoluene (1:3) and treated with 4N hydrogen chloride in ethyl acetatesolution to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-pyridylmethyl)piperazine dihydrochloride (123 mg).

[0909] [α]_(D) ²³: −28.30° (C=0.5, MeOH)

[0910] IR (Nujol): 3360, 2560, 1640, 1278, 1130 cm⁻¹

[0911] NMR (DMSO-d₆, δ): 2.0-2.3 (10H, m), 2.6-5.8 (9H, m), 6.6-8.7(10H, m)

[0912] MASS: 536 (M+1) (free)

EXAMPLE 71

[0913] Lindlar catalyst (Pd-CaCO₃-Pb(OAc)₂) (40 mg) was added to asolution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-morpholino-2-butynyl)piperazine in methanol (8 ml). The mixture was stirred for 2 hours underhydrogen at 25° C. and then filtered. The filtrate was concentratedunder reduced pressure and the resulting residue was chromatographed onsilica gel with dichloromethane-methanol (20:1) as eluent to givematerial which on treatment with 4N hydrogen chloride in ethyl acetatesolution afforded (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(Z)-4-morpholino-2-butenyl]piperazinedihydrochloride (104 mg).

[0914] [α]_(D) ²¹: ±0.40° (C=0.5, MeOH)

[0915] IR (Nujol): 3700-3150, 2750-2300, 1635, 1275, 1170, 1120 cm⁻¹

[0916] NMR (DMSO-d₆, δ): 3.00-4.10 (21H, m), 6.05-6.35 (2H, m),6.80-8.10 (8H, m), 10.72 (1H, s)

[0917] MASS: 595 (M+1) (free)

EXAMPLE 72

[0918] The following compound was obtained according to a similar mannerto that of Example 71.

[0919](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(Z)-4-morpholino-2-butenyl]piperazinedihydrochloride

[0920] mp: 243-246° C.

[0921] [α]_(D) ²¹: −5.30° (C=0.5, MeOH)

[0922] IR (Nujol): 3600-3150, 2600-2300, 1645, 1275, 1170, 1130 cm⁻¹

[0923] NMR (DMSO-d₆, δ): 2.10-2.20 (6H, m), 3.0-4.2 (21H, m), 6.05-5.35(2H, m), 6.80-7.10 (3H, m), 7.60 (2H, s), 8.09 (1H, s)

[0924]  The NMR spectrum of this compound was measured at 90° C.

[0925] MASS: 584 (M+1) (free)

EXAMPLE 73

[0926] A solution of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-morpholino-2-butynyl)piperazine in methanol (10 ml) was hydrogenated in the presence of 10%Pd-carbon (50 mg) at room temperature. After completion of the reaction(1 hour and 20 minutes), the reaction mixture was filtered and thenchromatographed on silica gel with dichloromethane-methanol (20:1) togive material which on treatment with 4N hydrogen chloride in ethylacetate solution afforded(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(4-morpholinobutyl)piperazine dihydrochloride (165.1 mg).

[0927] [α]_(D) ²¹: −7.10° (C=0.5, MeOH)

[0928] IR (Nujol): 3700-3150, 2720-2450, 1635, 1275, 1180-1080 cm⁻¹

[0929] NMR (DMSO-d₆, δ): 1.70-2.00 (4H, m), 2.95-5.20 (21H, m),6.60-8.25 (8H, m), 10.95 (1H, s), 11.10-11.80 (2H, m)

[0930] MASS: 597 (M+1) (free)

EXAMPLE 74

[0931] The following compound was obtained according to a similar mannerto that of Example 73.

[0932](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(5-morpholinopentyl)piperazine dihydrochloride

[0933] mp: 235-238° C.

[0934] [α]_(D) ²²: −13.90° (C=0.5, MeOH)

[0935] IR (Nujol): 3500-3100, 2600, 1630, 1270, 1180-1060 cm⁻¹

[0936] NMR (DMSO-d₆, δ): 1.2-2.0 (6H, m), 2.0-2.5 (8H, m), 2.6-5.2 (19H,m), 6.6-8.3 (6H, m), 11.26 (2H, m)

[0937] MASS: 600 (M+1) (free)

EXAMPLE 75

[0938] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (200 mg) and potassium carbonate (187 mg) were added to amixture of (E)-4-morpholino-2-butenyl chloride hydrochloride (105 mg)and acetonitrile (3 ml). The resulting mixture was heated at refluxtemperature under stirring. After 16 hours, the reaction mixture wasevaporated under reduced pressure and the residue was partitionedbetween ethyl acetate and water. The organic phase was separated andwashed with brine, and dried over magnesium sulfate. The solvent wasremoved in vacuo to leave an oil which was chromatographed on silica gelwith dichloromethane-methanol (50:1) as eluent to give material which ontreatment with 4N hydrogen chloride in ethyl acetate solution (0.2 ml)afforded (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-morpholino-2-butenyl]piperazinedihydrochloride (194 mg).

[0939] mp: 236-242° C.

[0940] [α]_(D) ^(19.6): −10.8° (C=0.3, MeOH)

[0941] IR (Nujol): 3350, 2900, 1645, 1275, 1185, 1170, 1135 cm⁻¹

[0942] NMR (DMSO-d₆, δ): 2.16 (3H, s), 2.20 (3H, s), 2.60-4.80 (19H, m),3.91 (4H, t, J=4.8Hz), 6.04-6.40 (2H, m), 6.74-7.15 (3H, m), 7.61 (2H,s), 8.08 (1H, s)

[0943]  The NMR spectrum of this compound was measured at 90° C.

[0944] MASS: 584 (M+1) (free)

EXAMPLE 76

[0945] The following compound was obtained according to a similar mannerto that of Example 75.

[0946](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(E)-4-morpholino-2-butenyl]piperazinedihydrochloride

[0947] mp: 123-128° C.

[0948] [α]_(D) ²⁰: −0.2° (C=0.3, MeOH)

[0949] IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1175, 1125 cm⁻¹

[0950] NMR (DMSO-d₆, δ): 2.60-5.00 (17H, m), 3.89 (4H, t, J=4.8Hz),6.00-6.40 (2H, m), 6.70-7.50 (5H, m), 7.80 (2H, s), 8.03 (1H, s), 10.74(1H, s)

[0951]  The NMR spectrum of this compound was measured at 90° C.

[0952] MASS: 595 (M+1) (free)

EXAMPLE 77

[0953] To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl) piperazine (0.2 g) and1-methyl-4-formyl-1H-pyrazole (0.05 g) in dichloromethane (2 ml) undernitrogen atmosphere was added sodium triacetoxyborohydride (151 mg) atroom temperature. After 4 hours, the reaction mixture was evaporatedunder reduced pressure, and ethyl acetate (20 ml) and aqueous sodiumhydrogen carbonate solution (10 ml) were added to the residue. Theorganic layer was separated and washed with brine, dried over magnesiumsulfate and then concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel using amixture of ethyl acetate and methanol (50:1). The obtained product wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazinehydrochloride (154 mg).

[0954] mp: 122-136° C.

[0955] [α]_(D) ^(18.8): −8.50° (C=0.3, MeOH)

[0956] IR (Nujol): 3350, 2750-2000, 1655, 1640, 1275, 1175, 1125 cm⁻¹

[0957] NMR (DMSO-d₆, δ): 2.80-5.20 (14H, m), 6.50-8.30 (10H, m), 10.90(1H, s), 11.40-11.90 (1H, br s)

[0958] MASS: 550 (M+1) (free)

EXAMPLE 78

[0959] A mixture of(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(methylsulfonyloxy)ethyl]piperazine(200 mg), 2-ethoxyethylamine (0.044 ml) and triethylamine (0.098 ml) inacetonitrile (5 ml) was refluxed for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure and the resulting residue waspartitioned between ethyl acetate and aqueous sodium hydrogen carbonatesolution. The organic layer was washed with brine and dried overmagnesium sulfate. After evaporation of the solvent, the residue waspurified by column chromatography on silica gel using a mixture ofdichloromethane and methanol (20:1) to afford an oily product, which wasdissolved in ethyl acetate and treated with 4N hydrogen chloride inethyl acetate solution to give(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(2-ethoxyethylamino)ethyl]piperazinedihydrochloride (64.5 mg)

[0960] [α]_(D) ²²: −6.70° (C=0.5, MeOH)

[0961] IR (Neat): 3400, 2650, 1640, 1430, 1280, 1170, 1150, 900 cm⁻¹

[0962] NMR (DMSO-d₆, δ): 1.63 (3H, m), 2.0-2.30 (6H, m), 2.6-5.3 (20H,m), 6.6-8.3 (6H, m), 9.2-9.6 (1H, br s), 11.2-1.8 (1H, br s)

[0963] MASS: 560(M+1) (free)

Preparation 8

[0964] To a mixture of N-(tert-butylcarbonyl)-4-fluoro-D-phenylalanine(5.25 g), N-benzylglycine benzyl ester hydrochloride (5.41 g) andtriethylamine (9.04 ml) in dichloromethane (50 ml) was added2-chloro-1-methylpyridinium iodide (5.21 g) at room temperature, and themixture was stirred for 2.5 hours. The mixture was evaporated underreduced pressure, and the resulting residue was dissolved into ethylacetate. The ethyl acetate solution was washed with diluted hydrochloricacid, saturated sodium hydrogen carbonate aqueous solution and brinesuccessively, and dried over magnesium sulfate. After evaporation of thesolvent, the resulting residue was chromatographed on a silica gel usingmixture of toluene and ethyl acetate as an eluent to give(2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)propanamide (9.62 g).

[0965] [α]_(D) ^(23.6): ±9.10° (C=0.5, MeOH)

[0966] IR (Nujol): 3350, 1735, 1680, 1650 cm⁻¹

[0967] NMR (DMSO-d₆, δ): 1.24, 1.30 (9H, 2s), 2.70-2.90 (2H, m),3.85-4.80 (5H, m), 5.12 (2H, d, J=3.2Hz), 6.95-7.45 (14H, m)

[0968] MASS: 521 (M+1)

Preparation 9

[0969] To an ice-cooled solution of(2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)propanamide (9.48 g) in dichloromethane (55 ml) was added 4N hydrogenchloride in dioxane solution (54.6 ml). The mixture was stirred at thesame temperature for 15 minutes and at room temperature for one hour.After removal of solvent by evaporation, excess aqueous sodium hydrogencarbonate solution was added to the resulting residue. The mixture waswarmed at near 50° C. for several minutes and the resulting precipitateswere collected by filtration and washed with water and dried in vacuo togive (3R)-1-benzyl-3-(4-fluorobenzyl) piperazine-2,5-dione (5.00 g).

[0970] [α]_(D) ^(27.3): −20.30° (C=0.5, MeOH)

[0971] IR (Nujol): 3200, 3050, 1665, 1220 cm⁻¹

[0972] NMR (DMSO-d₆, δ): 2.80 (1H, d, J=17.3Hz), 2.88 (1H, dd, J=13.7Hz,4.7Hz), 3.15 (1H, dd, J=13.7Hz, 4.1Hz), 3.53 (1H, d, J=17.3Hz), 4.15(1H, d, J=14.4Hz), 4.26 (1H, m), 4.63 (1H, d, J=14.4Hz), 6.80-7.40 (9H,m), 8.33 (1H, br s)

[0973] MASS: 313 (M+1)

Preparation 10

[0974] To an ice-cooled suspension of lithium aluminum hydride (1.2 g)in tetrahydrofuran (91 ml) was added (3R)-1-benzyl-3-(4-fluorobenzyl)piperazine-2,5-dione (4.95 g) by small portions. The mixture was stirredat the same temperature for 15 minutes and at room temperature for onehour. After removal of solvent by evaporation, aqueous sodium hydrogencarbonate solution was added to the resulting residue. The mixture waswarmed at near 50° C. for several minutes and the resulting precipitateswere collected by filtration, washed with water and dried in vacuo togive (3R)-1-benzyl-3-(4-fluorobenzyl) piperazine (4.60 g) as an oil.

[0975] IR (Neat): 3300, 1215 cm⁻¹

[0976] NMR (DMSO-d₆, δ): 1.90 (2H, m), 2.45-2.90 (5H, m), 3.30-3.45 (4H,m), 6.95-7.35 (9H, m)

[0977] MASS: 285 (M+1)

Preparation 11

[0978] A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (7.92 g), ammonium formate (2.38g) and 10% palladium charcoal (0.79 g) in a mixed solvent of ethanol (80ml) and water (8 ml) was stirred for 1.5 hours at 60° C. under nitrogenatmosphere. The reaction mixture was cooled to room temperature andfiltered through Celite® pad. The filtrate was concentrated underreduced pressure and the residue was dissolved into ethyl acetate. Thesolution was washed with water and brine successively, dried overmagnesium sulfate, and evaporated under reduced pressure to give(2R)-1-[3,5-bis (trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine(6.04 g) as an oil.

[0979] IR (Neat): 3300, 1630, 1150 cm⁻¹

[0980] NMR (DMSO-d₆, δ): 2.55-3.80 (8H, m), 4.25 (1H, m), 6.90-7.50 (5H,m), 7.64 (1H, br s), 8.13 (1H, br s)

[0981] MASS: 435 (M+1)

Preparation 12

[0982] The following compounds were prepared by a similar manner to thatof Preparation 8.

[0983] (1)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propanamide

[0984] [α]_(D) ^(24.0): +6.60° (C=0.5, MeOH)

[0985] IR (Neat): 3300, 1740, 1700, 1650, 1240 cm⁻¹

[0986] NMR (DMSO-d₆, δ): 1.27, 1.31 (9H, 2s), 2.76 (2H, m), 3.69, 3.70(3H, 2s), 3.95-4.90 (5H, m), 5.13 (2H, d, J=4.9Hz), 6.70-7.36 (14H, m)

[0987] MASS: 533 (M+1)

[0988] (2)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4-trifluoromethylphenyl)propanamide

[0989] [α]_(D) ^(26.4): +9.00° (C=0.5, MeOH)

[0990] IR (Nujol): 3350, 1735, 1720, 1670, 1650 cm⁻¹

[0991] NMR (DMSO-d₆, δ): 1.19, 1.27 (9H, 2s), 2.90 (2H, m), 4.00-4.75(5H, m), 5.12 (2H, s), 7.10-7.60 (15H, m)

[0992] MASS: 571 (M+1)

[0993] (3)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(1-naphthyl)propanamide

[0994] [α]_(D) ^(27.7): −0.60° (C=0.5, MeOH)

[0995] IR (Neat): 3300, 2970, 1740, 1700, 1645 cm⁻¹

[0996] NMR (DMSO-d₆, δ): 1.18, 1.26 (9H, 2s), 3.20-3.50 (2H, m),3.90-5.20 (7H, m), 7.10-8.10 (17H, m)

[0997] MASS: 553 (M+1)

Preparation 13

[0998] The following compounds were prepared by a similar manner to thatof Preparation 9.

[0999] (1) (3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione

[1000] [α]_(D) ^(27.9): −38.60° (C=0.5, MeOH)

[1001] IR (Nujol): 3250, 1680, 1640, 1245 cm⁻¹

[1002] NMR (DMSO-d₆, δ): 2.60 (1H, d, J=17.2Hz), 2.80 (1H, dd, J=13.6Hz,4.7Hz), 3.09 (1H, dd, J=13.6Hz, 3.8Hz), 3.46 (1H, d, J=17.2Hz), 3.67(3H, s), 4.11 (1H, d, J=14.4Hz), 4.22 (1H, br s), 4.65 (1H, d,J=14.4Hz), 6.63 (2H, d, J=8.7Hz), 6.93 (2H, d, J=8.7Hz), 7.10-7.40 (5H,m), 8.30 (1H, br s)

[1003] MASS: 325 (M+1)

[1004] (2) (3R)-1-Benzyl-3-(4-trifluoromethylbenzyl)piperazine-2,5-dione

[1005] [α]_(D) ^(26.8): −12.00° (C=0.5, MeOH)

[1006] IR (Nujol): 3250, 1680, 1650 cm⁻¹

[1007] NMR (DMSO-d₆, δ): 2.85 (1H, d, J=17.4Hz), 3.00 (1H, dd, J=13.4Hz,4.8Hz), 3.25 (1H, dd, J=13.4Hz, 4.4Hz), 3.59 (1H, d, J=17.4Hz), 4.08(1H, d, J=14.4Hz), 4.35 (1H, br s), 4.74 (1H, d, J=14.4Hz), 7.00-7.15(2H, m), 7.25-7.35 (5H, m), 7.48 (2H, d, J=8.1Hz), 8.41 (1H, s)

[1008] MASS: 363 (M+1)

[1009] (3) (3R)-1-Benzyl-3-(1-naphthylmethyl)piperazine-2,5-dione

[1010] IR (Nujol): 3250, 1685, 1655 cm⁻¹

[1011] NMR (DMSO-d₆, δ): 2.92 (1H, d, J=17.2Hz), 3.40-3.65 (3H, m), 4.31(3H, s), 7.03 (2H, m), 7.29 (5H, m), 7.54 (2H, m), 7.82 (1H, dd,J=6.5Hz, 3.0Hz), 7.94 (1H, m), 8.14 (1H, m), 8.31 (1H, d, J=3.0Hz)

[1012] MASS: 345 (M+1)

Preparation 14

[1013] The following compounds were prepared by a similar manner to thatof Preparation 10.

[1014] (1) (3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine

[1015] IR (Neat): 3250, 1240 cm⁻¹

[1016] NMR (DMSO-d₆, δ): 1.60-2.00 (4H, m), 2.40-2.90 (5H, m), 3.30-3.50(2H, m), 3.70 (3H, s), 6.81 (2H, d, J=8.6Hz), 7.07 (2H, d, J=8.6Hz),7.15-7.40 (6H, m)

[1017] MASS: 297 (M+1)

[1018] (2) (3R)-1-Benzyl-3-(4-trifluoromethylbenzyl)piperazine

[1019] [α]_(D) ^(27.2): −5.80° (C=0.5, MeOH)

[1020] IR (Neat): 3250, 2925, 2800, 1320 cm⁻¹

[1021] NMR (DMSO-d₆, δ): 1.72 (1H, t, J=10.0Hz), 1.91 (1H, m), 2.55-2.95(6H, m), 3.30-3.50 (3H, m), 7.15-7.35 (6H, m), 7.40 (2H, d, J=8.0Hz),7.60 (2H, d, J=8.0Hz)

[1022] MASS: 335 (M+1)

[1023] (3) (3R)-1-Benzyl-3-(1-naphthylmethyl)piperazine

[1024] [α]_(D) ^(27.6): −21.80° (C=0.5, MeOH)

[1025] IR (Neat): 3300, 3050, 2925, 2800 cm⁻¹

[1026] NMR (DMSO-d₆, δ): 1.75-2.05 (2H, m), 2.50-3.60 (9H, m), 7.10-7.65(9H, m), 7.77 (1H, d, J=7.9Hz), 7.90 (1H, m), 8.12 (1H, dd, J=7.1Hz,2.3Hz)

[1027] MASS: 317 (M+1)

Preparation 15

[1028] The following compounds were prepared by a similar manner to thatof Preparation 11.

[1029] (1) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)piperazine

[1030] [α]_(D) ^(28.1): −32.60° (C=0.5, MeOH)

[1031] IR (Neat): 3300, 1630, 1280 cm⁻¹

[1032] NMR (DMSO-d₆, δ) : 2.40-3.55 (9H, m), 3.72 (3H, s), 6.70-8.45(7H, m)

[1033] MASS: 447 (M+1)

[1034] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-trifluoromethylbenzyl)piperazine

[1035] NMR (DMSO-d₆, δ): 2.60-3.70 (9H, m), 7.15-7.40 (2H, m), 7.50-7.75(4H, m), 8.12 (1H, s)

[1036] MASS: 485 (M+1)

[1037] (3) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1-naphtnylmethyl)piperazine

[1038] [α]_(D) ^(28.1): −24.70° (C=0.5, MeOH)

[1039] IR (Neat): 3340, 3050, 2950, 2825, 1630 cm⁻¹

[1040] NMR (DMSO-d₆, δ): 2.50-4.30 (9H, m), 7.10-8.55 (10H, m)

[1041] MASS: 467 (M+1)

Preparation 16

[1042] A mixture of 1-methyl-1H-pyrazole-4-carboxaldehyde (2.0 g) andtriethyl phosphonoacetate (4.52 g) in N,N-dimethylformamide (20 ml) wasstirred under ice-cooling. After several minutes, sodium hydride (1.09g, 60% in mineral oil) was added to the mixture, which was stirred for 1hour at the same temperature. The resulting mixture was poured intoice-water, neutralized with aqueous ammonium acetate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate and concentrated under reduced pressure.The resulting residue was chromatographed on a silica gel using amixture of hexane and ethyl acetate as an eluent to give ethyl(E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate.

[1043] IR (Nujol): 2975, 1700, 1635 cm⁻¹

[1044] NMR (DMSO-d₆, δ): 1.32 (3H, t, J=7.1Hz), 4.23 (2H, q, J=7.1Hz),6.16 (1H, d, J=16.0Hz), 7.54 (1H, s), 7.55 (1H, d, J=16.0Hz), 7.69 (1H,s)

Preparation 17

[1045] A solution of 2-(E)-3-(1-methyl-1H-pyrazol-4-yl)acrylate (1.04 g)in tetrahydrofuran (50 ml) was hydrogenated over 10% palladium charcoal(0.2 g) at room temnerature at 2 atm of hydrogen. After removal ofcatalyst by filtration through Celite® pad the filtrate was concentratedunder reduced pressure to give ethyl 3-(1-methyl-1H-pyrazol-4-yl)propionate.

[1046] IR (Neat): 2950, 1725 cm⁻¹

[1047] NMR (DMSO-d₆, δ): 1.24 (3H, t, J=7.1Hz), 2.50 (2H, t, J=7.5Hz),2.78 (2H, t, J=7.5Hz), 3.84 (3H, s), 4.13 (2H, q, J=7.1Hz), 7.18 (1H,s), 7.31 (1H, s)

[1048] MASS: 183 (M+1)

Preparation 18

[1049] To an ice-cooled solution of ethyl 3-(1-methyl-1H-pyrazol-4-yl)propionate (1.05 g) in tetrahydrofuran (10 ml) was added lithiumaluminum hydride (0.22 g) under nitrogen atmosphere. After the mixturewas stirred for 30 minutes, water and 15% sodium hydroxide aqueoussolution were added successively to the mixture. The resultingprecipitates were filtered off through Celite® pad and the filtrate wasextracted with ethyl acetate. The organic layer was washed with water,dried over magnesium sulfate and concentrated under reduced pressure togive 3-(1-methyl-1H-pyrazol-4-yl)-1-propanol.

[1050] IR (Neat): 3300, 2930 cm⁻¹

[1051] NMR (DMSO-d₆, δ): 1.87 (2H, m), 2.55 (2H, t, J=7.6Hz), 3.68 (2H,t, J=6.1Hz), 3.85 (3H, s), 7.16 (1H, s), 7.31 (1H, s)

[1052] MASS: 141 (M+1)

Preparation 19

[1053] To a solution of oxalyl chloride (0.361 ml) in dichloromethane(10 ml) cooled below −65° C. with a dry ice-acetone bath, a solution ofdimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) was added withefficient stirring over 10 minutes. After 20 minutes below −65° C., asolution of 3-(1-methyl-1H-pyrazol-4-yl)-1-propanol in dichloromethane(2 ml) was added to the mixture over 10 minutes below −65° C. and themixture was stirred at the same temperature for 20 minutes and then at−45˜−40° C. for 30 minutes. After addition of triethylamine dropwise tothe mixture over 10 minutes followed by stirring for 15 minutes, 1Nhydrochloric acid solution was added to the mixture. The resultingmixture was extracted with a mixture of dichloromethane and methanolseveral times. The extract was concentrated under reduced pressure andthe resulting residue was chromatographed on a silica gel using amixture of dichloromethane and methanol as an eluent to give3-(1-methyl-1H-pyrazol-4-yl)-1-propanal.

[1054] IR (Neat): 2925, 1720 cm⁻¹

[1055] NMR (DMSO-d₆, δ): 2.65-2.90 (4H, m), 3.86 (3H, s), 7.17 (1H, s),7.32 (1H, s), 9.80 (1H, s)

[1056] MASS: 139 (M+1)

EXAMPLE 79

[1057] To a mixture of 3,5-bis(trifluoromethyl)benzoic acid (4.13 g) andpyridine (0.041 ml) in tetrahydrofuran (12.5 ml) was added oxalylchloride (3.25 g) over 15 minutes at 22-38° C. and the mixture wasstirred at 55° C. for 4 hours. The acid chloride solution obtained aboveprocedure was added to an ice-cooled solution of(3R)-1-benzyl-3-(4-fluorobenzyl) piperazine (4.51 g) and triethylamine(4.83 g) in dichloromethane (45 ml) under 5° C. for 30 minutes. Afterbeing stirred for 2 hours at room temperature, the mixture was washedwith water and brine successively, and dried over magnesium sulfate.After evaporation of the solvent, the resulting residue waschromatographed on a silica gel using a mixture of toluene and ethylacetate as an eluent to give(2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (0.87 g) as a syrup.

[1058] [α]_(D) ^(27.5): −11.50° (C=0.5, MeOH)

[1059] IR (Neat): 1740, 1150 cm⁻¹

[1060] NMR (DMSO-d₆, δ): 2.00-4.40 (11H, m), 6.80-7.50 (10H, m), 7.74(1H, br s), 8.13 (1H, br)

[1061] MASS: 525 (M+1)

EXAMPLE 80

[1062] The following compounds were prepared by a similar manner to thatof Example 79.

[1063] (1)(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)piperazine

[1064] [α]_(D) ^(28.0): −21.40° (C=0.5, MeOH)

[1065] IR (Neat): 1740, 1640, 1270 cm⁻¹

[1066] NMR (DMSO-d₆, δ): 1.70-2.40 (3H, m), 2.60-3.80 (11H, m),6.60-7.60 (10H, m), 7.65-8.55 (2H, m)

[1067] MASS: 537 (M+1)

[1068] (2)(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-trifluoromethylbenzyl)piperazine

[1069] IR (Neat): 2950, 2800, 1765, 1740, 1640 cm⁻¹

[1070] NMR (DMSO-d₆, δ): 1.70-4.30 (11H, m), 7.13 (1H, d, J=7.8Hz),7.20-7.70 (10H, m), 8.13 (1H, d, J=7.8Hz)

[1071] MASS: 575 (M+1)

[1072] (3)(2R)-4-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1-naphthylmethyl)piperazine

[1073] [α_(D) ^(27.5): −9.70° (C=0.5, MeOH)

[1074] IR (Nujol): 1640 cm⁻¹

[1075] NMR (DMSO-d₆, δ): 2.00-4.40 (11H, m), 7.00-8.55 (15H, m)

[1076] MASS: 557 (M+1)

EXAMPLE 81

[1077] The following compound was prepared by a similar manner to thatof Example 66.

[1078] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(cis-2,6-dimethylmorpholino)propyl]piperazinedihydrochloride

[1079] [α]_(D) ^(21.0): −11.10° (C=0.5, MeOH)

[1080] IR (Neat): 3400, 2550, 2450, 1640, 1430, 1280, 1175, 1130 cm⁻¹

[1081] NMR (DMSO-d₆, δ): 1.14 (6H, m), 2.05-5.24 (19H, m), 2.10 (3H, s),2.18 (3H, s), 6.64-8.24 (6H, m)

[1082] MASS: 600 (M+1) (free)

[1083] Anal. Calcd. for C₃₁H₃₉F₆N₃O₂·2HCl·2.35H₂O

[1084] C 52.08, H 6.29, N 5.77

[1085] Found: C 52.08, H 6.44, N 5.88

EXAMPLE 82

[1086] The following compounds were obtained according to a similarmanner to that of Example 23.

[1087] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[N-(3-pyridylmethyl)-3-aminopropyl]piperazinetrihydrochloride

[1088] [α]_(D) ^(28.4): −13.60° (C=0.25, MeOH)

[1089] IR (Neat): 3600-3100, 2800-1950, 1270, 1125 cm⁻¹

[1090] NMR (DMSO-d₆, δ): 2.09-5.20 (24H, m), 6.60-9.00 (10H, m)

[1091] MASS: 593 (M+1) (free)

[1092] Anal. Calcd. for C₂₁H₃₄F₆N₄O·3HCl·4H₂O :

[1093] C 48.10, H 5.86, N 7.24

[1094] Found: C 47.89, H 5.75, N 7.02

[1095] (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethybenzyl)-4-(N-morpholino-2-aminoethyl)piperazine dihydrochloride

[1096] [α]_(D) ^(28.5): −26.80° (C=0.25, MeOH)

[1097] IR (Neat): 3600-3000, 2800-2000, 1630, 1274, 1120 cm⁻¹

[1098] NMR (DMSO-d₆, δ): 2.02-5.20 (28H, m), 6.50-8.30 (6H, m)

[1099] MASS: 573 (M+1) (free)

[1100] Anal. Calcd. for C₂₈H₃₄F₆N₄O₂·2HCl·9/2H₂O·1/4CH₃CO₂ C₂H₅:

[1101] C 46.53, H 6.33, N 7.48

[1102] Found: C 46.64, H 6.23, N 6.67

[1103] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(N-morpholino-4-amino-2-butynyl)piperazine dihydrochloride

[1104] [α]_(D) ^(28.0): −9.80° (C=0.25, MeOH)

[1105] IR (Neat): 3600-3000, 2600-1950, 1630, 1273, 1120 cm⁻¹

[1106] NMR (DMSO-d₆, δ): 2.10-5.20 (28H, m), 6.20-8.30 (6H, m)

[1107] MASS: 597 (M+1) (free)

[1108] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[N-methyl-N-(3-pyridylmethyl)-2-aminoethyl]piperazinetrihydrocloride

[1109] [α]_(D) ^(28.4): −11.80° (C=0.25, MeOH)

[1110] IR (Nujol): 3600-3100, 2700-1950, 1630, 1275, 1122 cm⁻¹

[1111] NMR (DMSO-d₆, δ): 2.10-5.20 (24H, m), 6.60-7.80 (6H, m),8.10-8.35 (2H, m), 8.70-8.95 (2H, m)

[1112] MASS: 593 (M+1) (free)

[1113] Anal. Calcd. for C₃₁H₃₄F₆N₄O·3HCl·7/2H₂O :

[1114] C 48.67, H 5.80, N 7.32

[1115] Found: C 48.88, H 5.88, N 6.79

[1116] (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-N-(3-pyridylmethyl)-4-amino-2-butenyl]piperazinetrihydrochloride

[1117] [α]_(D) ^(28.5): −10.40° (C=0.25, MeOH)

[1118] IR (Neat): 3600-3100, 2800-1950, 1630, 1274, 1124 cm⁻¹

[1119] NMR (DMSO-d₆, δ): 2.09-5.20 (22H, m), 6.05-6.25 (2H, m),6.60-9.00 (10H, m)

[1120] MASS: 605 (M+1) (free)

[1121] Anal. Calcd. for C₃₂H₃₄F₆N₄O·3HCl·5H₂O :

[1122] C 47.80, H 5.89, N 6.97

[1123] Found: C 47.81, H 5.53, N 6.48

[1124] (6)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-N-morpholino-4-amino-2-butenyl]piperazinedihydrochloride

[1125] [α]_(D) ^(28.5): −6.40° (C=0.25, MeOH)

[1126] IR (Nujol): 3600-3000, 2750-1950, 1620, 1273, 1120 cm⁻¹

[1127] NMR (DMSO-d₆, δ): 2.09-5.20 (28H, m), 5.80-8.30 (8H, m)

[1128] MASS: 599 (M+1) (free)

[1129] Anal. Calcd. for C₃₀H₃₆F₆N₄O₂·2HCl·7/2H₂O:

[1130] C 49.05, H 6.17, N 7.63

[1131] Found: C 49.15, H 6.16, N 7.41

[1132] (7)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[N-(3-pyridylmethyl)-2-aminoethyl]piperazine trihydrochloride

[1133] [α]_(D) ^(28.5): −11.00° (C=0.25, MeOH)

[1134] IR (Neat): 3600-3100, 2800-1950, 1630, 1273, 1120 cm⁻¹

[1135] NMR (DMSO-d₆, δ):2.50-5.20 (16H, m), 7.00-9.00 (14H, m)

[1136] MASS: 601 (M+1) (free)

[1137] Anal. Calcd. for C₃₂H₃₀F₆N₄O·3HCl·4H₂O:

[1138] C 49.15, H 5.28, N 7.16

[1139] Found: C 49.26, H 5.24, N 6.80

[1140] (8)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(N-morpholino-2-aminoethyl)piperazine dihydrochloride

[1141] [α]_(D) ^(28.6): −34.80° (C=0.25, MeOH)

[1142] IR (Neat): 3600-3100, 2800-1950, 1630, 1273, 1120 cm⁻¹

[1143] NMR (DMSO-d₆, δ):2.50-5.30 (22H, m), 7.00-8.20 (10H, m)

[1144] MASS: 595 (M+1) (free)

[1145] Anal. Calcd. for C₃₀H₃₂F₆N₄O₂·2HCl·11/3H₂O:

[1146] C 49.12, H 5.68, N 7.64

[1147] Found: C 49.04, H 5.57, N 7.39

[1148] (9)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(N-morpholino-3-aminopropyl)piperazine dihydrochloride

[1149] [α]_(D) ^(28.6): −40.10° (C=0.25, MeOH)

[1150] IR (Nujol): 3650-3100, 2800-1970, 1636, 1275, 1123 cm⁻¹

[1151] NMR (DMSO-d₆, δ): 2.20-5.30 (24H, m), 7.00-8.20 (10H, m),10.60-11.80 (3H, m)

[1152] MASS: 610 (M+1) (free)

[1153] Anal. Calcd. for C₃₁H₃₄F₆N₄O₂·2HCl·3H₂O:

[1154] C 50.62, H 5.75, N 7.62

[1155] Found: C 50.72, H 5.58, N 6.99

[1156] (10) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(E)-N-(3-pyridylmethyl)-4-amino-2-butenyl]piperazinetrihydrochloride

[1157] [α]_(D) ^(28.4): −20.40° (C=0.25, MeOH)

[1158] IR (Nujol): 3650-3100, 2750-1930, 1620, 1272, 1122 cm⁻¹

[1159] NMR (DMSO-d₆, δ): 3.00-5.30 (16H, m), 6.00-6.30 (2H, m),7.00-9.10 (14H, m)

[1160] MASS: 627 (M+1) (free)

[1161] Anal. Calcd. for C₃₄H₃₂F₆N₄O·3HCl·2H₂O:

[1162] C 52.89, H 5.09, N 7.26

[1163] Found: C 52.73, H 5.09, N 7.16

[1164] (11)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[(E)-N-morpholino-4-amino-2-butenyl]piperazinedihydrochloride

[1165] [α]_(D) ^(28.6): −13.00° (C=0.25, MeOH)

[1166] IR (Neat): 3650-3000, 2750-1970, 1630, 1274 cm⁻¹

[1167] NMR (DMSO-d₆, δ): 2.80-5.30 (22H, m), 6.15-6.50 (2H, m),7.00-8.25 (10H, m)

[1168] MASS: 621 (M+1) (free)

[1169] (12)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-[N-(3-pyridylmethyl)-3-aminopropyl]piperazinetrihydrochloride

[1170] [α]_(D) ^(28.6): −24.60° (C=0.25, MeOH)

[1171] IR (Nujol): 3600-3100, 2750-1950, 1630, 1273, 1121 cm⁻¹

[1172] NMR (DMSO-d₆, δ):2.20-5.30 (18H, m), 7.00-9.10 (14H, m)

[1173] MASS: 615 (M+1) (free)

[1174] Anal. Calcd. for C₃₃H₃₂F₆N₄O·3HCl·10/3H₂O:

[1175] C 50.56, H 5.36, N 7.15

[1176] Found: C 50.53, H 5.38, N 6.94

EXAMPLE 83

[1177] The following compounds were obtained according to a similarmanner to that of Example 35.

[1178] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(4-homomorpholino-2-butynyl)piperazine dihydrochloride

[1179] [α]_(D) ^(28.0): −19.80° (C=0.5, MeOH)

[1180] IR (Neat): 3400, 2500, 1640, 1430, 1280, 1175, 1130 cm⁻¹

[1181] NMR (DMSO-d₆, δ):1.95-5.34 (23H, m), 7.05-8.20 (10H, m)

[1182] MASS: 618 (M+1) (free)

[1183] Anal. Calcd. for C₃₃H₃₃F₆N₃O₂·2HCl·2.9H₂O:

[1184] C 53.37, H 5.53, N 5.66

[1185] Found: C 53.38, H 5.47, N 5.67

[1186] (2) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylbenzyl)-4-[(E)-4-morpholino-2-butenyl]piperazinedihydrochloride

[1187] [α]_(D) ^(28.0): −4.50° (C=0.5, MeOH)

[1188] IR (Nujol): 2400, 1645, 1275, 1135 cm⁻¹

[1189] NMR (DMSO-d₆, δ): 2.20 (3H, s), 2.80-5.20 (21H, m), 6.00-8.26(8H, m)

[1190] MASS: 588 (M+1) (free)

[1191] Anal. Calcd. for C₂₉H₃₂F₇N₃O₂·2HCl:

[1192] C 52.74, H 5.19, N 6.36

[1193] Found: C 52.39, H 5.20, N 6.29

[1194] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-fluoro-4-methylbenzyl)-4-[(E)-4-chloro-2-butenyl]piperazine

[1195] IR (Neat): 1640, 1430, 1275, 1130 cm⁻¹

[1196] NMR (DMSO-d₆, δ): 1.91-4.93 (13H, m), 5.71-8.20 (8H, m)

[1197] MASS: 537 (M+1)

[1198] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-morpholino-2-butynyl]piperazinedihydrochloride

[1199] mp: 98-101° C.

[1200] NMR (DMSO-d₆, δ): 2.0-5.2 (25H, m), 5.74 (1H, br d), 5.89 (1H, brd), 6.6-8.2 (6H, m)

[1201] MASS: 578 (M+1) (free)

[1202] Anal. Calcd. for C₃₁H₃₃F₆N₃O·2HCl·2H₂O:

[1203] C 54.23, H 5.73, N 6.12

[1204] Found: C 53.99, H 5.83, N 5.93

EXAMPLE 84

[1205] The following compounds were obtained according to a similarmanner to that of Example 50.

[1206] (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride

[1207] mp: 180° C. (dec.)

[1208] [α]_(D) ^(28.0): +5.00° (C=0.5, MeOH)

[1209] IR (Nujol): 3350, 1630, 1125 cm⁻¹

[1210] NMR (DMSO-d₆, δ): 2.60-4.30 (21H, m), 6.85-7.25 (3H, m), 7.46(2H, br s), 7.75 (1H, br s), 8.16 (1H, d, J=9.4Hz)

[1211] MASS: 588 (M+1) (free)

[1212] Anal. Calcd. for C₂₈H₂₈F₇N₃OS·2HCl·H₂O:

[1213] C 49.56, H 4.75, N 6.19

[1214] Found: C 49.47, H 5.13, N 5.93

[1215] (2)(2)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride

[1216] mp: 197° C. (dec.)

[1217] [α]_(D) ^(28.1): −8.60° C=0.5, MeOH)

[1218] IR (Nujol): 2500, 1640, 1275 cm⁻¹

[1219] NMR (DMSO-d₆, δ): 2.60-4.70 (24H, m), 6.70-8.30 (7H, m)

[1220] MASS: 600 (M+1) (free)

[1221] Anal. Calcd. for C₂₉H₃₁F₆N₃O₂S·2HCl·1.3H₂O:

[1222] C 50.05, H 5.16, N 6.04

[1223] Found: C 50.06, H 5.36, N 5.77

[1224] (3)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-trifluoromethylbenzyl)-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride

[1225] mp: 173° C. (dec.)

[1226] [α]_(D) ^(28.0): +9.60° (C=0.5, MeOH)

[1227] IR (Nujol): 2400, 1640 cm⁻¹

[1228] NMR (DMSO-d₆, δ): 2.70-5.30 (21H, m), 7.22 (1H, d, J=7.7Hz), 7.41(1H, s), 7.50-7.80 (4H, m), 8.18 (1H, d, J=7.0Hz)

[1229] MASS: 638 (M+1) (free)

[1230] Anal. Calcd. for C₂₉H₂₈F₉N₃OS·2HCl·1.3H₂O:

[1231] C 47.46, H 4.48, N 5.73

[1232] Found: C 47.43, H 4.51, N 5.51

[1233] (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1-naphthylmethyl)-4-(4-thiomorpholino-2-butynyl)piperazine dihydrochloride

[1234] mp: 191° C. (dec.)

[1235] [α]_(D) ^(28.0): +15.60° (C=0.5, MeOH)

[1236] IR (Nujol): 2500, 1635 cm⁻¹

[1237] NMR (DMSO-d₆, δ):2.65-4.80 (21H, m), 7.10-8.60 (10H, m)

[1238] MASS: 620 (M+1) (free)

[1239] Anal. Calcd. for C₃₂H₃₁F₆N₃OS·2HCl·0.4H₂O:

[1240] C 54.92, H 4.87, N 6.00

[1241] Found: C 54.88, H 5.04, N 5.65

EXAMPLE 85

[1242] The following compound was obtained according to a similar mannerto that of Example 51.

[1243](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(1-methyl-1H-pyrazol-4-yl)propyl]piperazine hydrochloride

[1244] mp: 163-165° C.

[1245] [α]_(D) ^(25.3): −19.80° (C=0.5, MeOH)

[1246] IR (Nujol): 2550, 1635 cm⁻¹

[1247] NMR (DMSO-d₆, δ): 1.90-2.25 (6H, m), 3.00-4.00 (15H, br),6.65-8.25 (8H, m)

[1248] MASS: 567 (M+1) (free)

[1249] Anal. Calcd. for C₂₉H₃₂F₆N₄O·HCl·H₂O:

[1250] C 56.08, H 5.68, N 9.02

[1251] Found: C 56.44, H 5.76, N 8.98

EXAMPLE 86

[1252] The following compound was obtained according to a similar mannerto that of Example 61.

[1253] (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[4-(3,3-dimethylmorpholino)-2-butenyl]piperazine dihydrochloride

[1254] mp: 210° C. (dec.)

[1255] [α]_(D) ^(28.4): +0.63° (C=0.11, MeOH)

[1256] IR (Nujol): 3660-3300, 2700-2300, 1640, 1445, 1430, 1370, 1270cm⁻¹

[1257] NMR (DMSO-d₆, δ): 1.30-1.55 (6H, m), 2.85-5.25 (19H, m),6.05-6.30 (2H, m), 6.65-8.25 (8H, m), 10.97 (1H, br s), 11.40-12.20 (2H,m)

[1258] MASS: 623 (M+1) (free)

EXAMPLE 87

[1259] The following compound was obtained according to a similar mannerto that of Example 54.

[1260](2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3-pyridyl)propyl]piperazinedihydrochloride

[1261] mp: 163-168° C.

[1262] [α]_(D) ^(24.7): +5.77° (C=1.3, MeOH)

[1263] IR (Nujol): 3600-3300, 2700-2300, 1635, 1445, 1430, 1370, 1280cm⁻¹

[1264] NMR (DMSO-d₆, δ): 1.92-5.22 (29H, m), 6.56-8.28 (6H, m), 11.43(2H, br s)

[1265] MASS: 564 (M+1) (free)

[1266] Anal. Calcd. for C₃₀H₃₁F₆N₃O·2HCl·2.4H₂O:

[1267] C 53.01, H 5.60, N 6.18

[1268] Found: C 53.04, H 5.98, N 5.77

1. A compound of the formula

wherein Y is bond or lower alkylene, R¹ is aryl which may have suitablesubstituent(s), R² is aryl or indolyl each of which may have suitablesubstituent(s), R³ is hydrogen or lower alkyl, R⁴ ischloro(lower)alkenyl; chloro(lower)alkynyl;pyridyl(lower)alkylamino(lower)alkyl;pyridyl(lower)alkylamino(lower)alkenyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl;bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;phenyl(lower)alkyl which may have lower alkanoyl, amino, loweralkanoylamino, di(lower)alkylaminocarbonyl or nitro; loweralkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;benzoyl(lower)alkyl which has lower alkyl, chlorine ordi(lower)alkylamino; benzoyl(lower)alkyl which has halogen and loweralkyl; dihalobenzoyl(lower)alkyl; di(lower)alkylbenzoyl(lower)alkyl;3-fluorobenzoyl(lower)alkyl; 3-(4-fluorobenzoyl)propyl;4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;(2-pyridyl)(lower)alkyl; (3-pyridyl)propyl; (3-pyridyl)(lower)alkynyl;imidazolyl(lower)alkyl which may have lower alkyl; pyrazolyl(lower)alkylwhich may have lower alkyl; thiomorpholinylcarbonyl(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; orthienylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkynyl,1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl, saturatedheterocyclic(lower)alkyl, saturated heterocyclic(lower)alkenyl,saturated heterocyclic(lower)alkynyl, saturatedheterocyclicamino(lower)alkyl, saturated heterocyclicamino(lower)alkenylor saturated heterocyclicamino(lower)alkynyl, each of which may havesuitable substituent(s), and a pharmaceutically acceptable salt thereof.2. The compound of claim 1, in which Y is lower alkylene, R¹ is C₆-C₁₀aryl which may have 1 to 3 mono(or di or tri)halo(lower)alkyl, R² isC₆-C₁₀ aryl or indolyl, each of which may have 1 to 3 suitablesubstituent(s) selected from the group consisting of lower alkyl, loweralkoxy, mono(or di or tri)halo(lower)alkyl and halogen, R³ is hydrogen,and R⁴ is chloro(lower)alkenyl; chloro(lower)alkynyl;pyridyl(lower)alkylamino(lower)alkyl;pyridyl(lower)alkylamino(lower)alkenyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl;bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;phenyl(lower)alkyl which may have lower alkanoyl, amino, loweralkanoylamino, di(lower)alkylaminocarbonyl or nitro; loweralkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;benzoyl(lower)alkyl which has lower alkyl, chlorine ordi(lower)alkylamino; benzoyl(lower)alkyl which has halogen and loweralkyl; dihalobenzoyl(lower)alkyl; di(lower)alkylbenzoyl(lower)alkyl;3-fluorobenzoyl(lower)alkyl; 3-(4-fluorobenzoyl)propyl;4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;(2-pyridyl)(lower)alkyl; (3-pyridyl)propyl; (3-pyridyl)(lower)alkynyl;imidazolyl(lower)alkyl which may have lower alkyl; pyrazolyl(lower)alkylwhich may have lower alkyl; thiomorpholinylcarbonyl(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; orthienylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkynyl,1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl,saturated heterocyclic(lower)alkenyl, saturatedheterocyclic(lower)alkynyl, saturated heterocyclicamino(lower)alkyl,saturated heterocyclicamino(lower)alkenyl or saturatedheterocyclicamino(lower)alkynyl [wherein “saturated heterocyclic moiety”is saturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s); saturated 3 to 8-membered heteromonocyclic groupcontaining 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s); saturated3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s)and 1 to 3 nitrogen atom(s); or saturated heterocyclic group of theformula:

 each of which may have 1 to 3 suitable substituent(s) selected from thegroup consisting of cyclo(lower)alkyl, lower alkanoyl, lower alkyl,mono(or di or tri)halo(lower)alkyl, lower alkoxy, loweralkoxy(lower)alkyl, halogen, C₆-C₁₀ aryl, cyano, oxo and bivalent groupof the formula:


3. The compound of claim 2, in which Y is lower alkylene, R¹ is phenylwhich may have 1 or 2 mono(or di or tri)halo(lower)alkyl, R² is phenyl,naphthyl or indolyl, each of which may have 1 or 2 suitablesubstituent(s) selected from the group consisting of lower alkyl, loweralkoxy, mono(or di or tri)halo(lower)alkyl and halogen, R³ is hydrogen,and R⁴ is chloro(lower)alkenyl; chloro(lower)alkynyl;pyridyl(lower)alkylamino(lower)alkyl;pyridyl(lower)alkylamino(lower)alkenyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl;bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower)alkyl;hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;phenyl(lower)alkyl which may have lower alkanoyl, amino, loweralkanoylamino, di(lower)alkylaminocarbonyl or nitro; loweralkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;benzoyl(lower)alkyl which has lower alkyl, chlorine ordi(lower)alkylamino; benzoyl(lower)alkyl which has halogen and loweralkyl; dihalobenzoyl(lower)alkyl; di(lower)alkylbenzoyl(lower)alkyl;3-fluorobenzoyl(lower)alkyl; 3-(4-fluorobenzoyl)propyl;4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;(2-pyridyl)(lower)alkyl; (3-pyridyl) propyl; (3-pyridyl)(lower)alkynyl;imidazolyl(lower)alkyl which may have lower alkyl; pyrazolyl(lower)alkylwhich may have lower alkyl; thiomorpholinylcarbonyl(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; orthienylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkynyl,1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl,saturated heterocyclic(lower)alkenyl, saturatedheterocyclic(lower)alkynyl, saturated heterocyclicamino(lower)alkyl,saturated heterocyclicamino(lower)alkenyl or saturatedheterocyclicamino(lower)alkynyl [wherein “saturated heterocyclic moiety”is pyrrolidinyl, piperidyl, piperazinyl, hexamethyleneimino,morpholinyl, homomorpholinyl, thiomorpholinyl or3-azabicyclo[3.2.2]non-3-yl], each of which may have 1 or 2 suitablesubstituent(s) selected from the group consisting of cyclo(lower)alkyl,lower alkanoyl, lower alkyl, mono(or di or tri)halo(lower)alkyl, loweralkoxy, lower alkoxy(lower)alkyl, halogen, phenyl, cyano, oxo andbivalent group of the formula:


4. The compound of claim 3, in which Y is lower alkylene, R¹ is phenylwhich may have 1 or 2 mono(or di or tri)halo(lower)alkyl, R² is phenylwhich may have 1 or 2 suitable substituent(s) selected from the groupconsisting of lower alkyl, lower alkoxy, mono(or di ortri)halo(lower)alkyl and halogen, naphthyl or indolyl, R³ is hydrogen,and R⁴ is (2-pyridyl)(lower)alkyl; (3-pyridyl)propyl;(3-pyridyl)(lower)alkynyl; imidazolyl(lower)alkyl which may have loweralkyl; pyrazolyl(lower)alkyl which may have lower alkyl;pyridyl(lower)alkylamino(lower)alkyl;pyridyl(lower)alkylamino(lower)alkenyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl;bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino(lower)alkyl;1,2,3,6-tetrahydropyridyl(lower)alkyl;1,2,3,6-tetrahydropyridyl(lower)alkynyl;1,2,3,4-tetrahydroisoquinolyl(lower)alkyl; or4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower) alkyl.
 5. The compoundof claim 3, in which Y is lower alkylene, R¹ is phenyl which may have 1or 2 mono(or di or tri)halo(lower)alkyl, R² is phenyl which may have 1or 2 suitable substituent(s) selected from the group consisting of loweralkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen,naphthyl or indolyl, R³ is hydrogen, and R⁴ is morpholinyl(lower)alkylwhich may have 1 or 2 lower alkyl; homomorpholinyl(lower)alkyl;rhiomorpholinyl(lower)alkyl; (hexamethyleneimino)(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl; piperazinyl(lower)alkyl whichmay have phenyl or cyclo(lower)alkyl; inorpholinyl(lower)alkenyl whichmay have 1 or 2 lower alkyl; morpholinyl(lower)alkynyl which may have 1or 2 lower alkyl, lower alkoxy(lower)alkyl or mono(or di ortri)halo(lower)alkyl; thiomorpholinyl(lower) alkenyl;thiomorpholinyl(lower)alkynyl; pyrrolidinyl(lower)alkynyl which may havelower alkoxy(lower)alkyl; piperazinyl(lower)alkynyl which may have cyclo(lower)alkyl; morpholinylamino(lower)alkyl;morpholinylamino(lower)alkenyl; morpholinylamino(lower)alkynyl;[spiro[indan-1,4′-piperidinel-1′-yl](lower)alkyl; piperidyl(lower)alkylwhich has phenyl, lower alkoxy, lower alkanoyl, piperidyl or oxo; orpiperidyl(lower)alkyl which has phenyl and cyano.
 6. The compound ofclaim 5, in which Y is lower alkylene, R¹ is phenyl which may have 1 or2 mono(or di or tri) halo(lower)alkyl, R² is phenyl which may have 1 or2 suitable substituent(s) selected from the group consisting of loweralkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl and halogen,naphthyl or indolyl, R³ is hydrogen, and R⁴ is morpholinyl(lower)alkylwhich may have 1 or 2 methyl; homomorpholinyl(lower)alkyl;thiomorpholinyl(lower)alkyl; (hexamethyleneimino)(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)(lower)alkyl; piperazinyl(lower)alkyl whichhas phenyl or cyclohexyl; morpholinyl(lower)alkenyl which may have 1 or2 methyl; morpholinyl(lower)alkynyl which may have 1 or 2 methyl,methoxymethyl or fluoromethyl; thiomorpholinyl(lower)alkenyl;thiomorpholinyl(lower)alkynyl; pyrrolidinyl(lower)alkynyl which may havemethoxymethyl; piperazinyl(lower)alkynyl which may have cyclohexyl;morpholinylamino(lower)alkyl; morpholinylamino(lower)alkenyl;morpholinylamino(lower)alkynyl;[spiro[indan-1,4′-piperidine]-1′-yl](lower)alkyl; piperidyl(lower)alkylwhich has phenyl, methoxy, acetyl, piperidyl or oxo; orpiperidyl(lower)alkyl which has phenyl and cyano.
 7. The compound ofclaim 6, in which Y is methylene, R¹ is bis(trifluoromethyl)phenyl, R²is phenyl or naphthyl, each of which may have 1 or 2 suitablesubstituent(s) selected from the group consisting of methyl, methoxy,trifluoromethyl and fluorine, or indolyl, R³ is hydrogen, and R⁴ isthiomorpholinyl(C₁-C₄)alkyl; morpholinyl(C₂-C₄)alkenyl which may have 1or 2 methyl; morpholinyl(C₂-C₅)alkynyl which may have 1 or 2 methyl,methoxymethyl or fluoromethyl; or morpholinylamino(C₁-C₄)alkyl.
 8. Thecompound of claim 7, which is selected from the group consisting of (1)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)- piperazine, (2)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2-butynyl)-2-(2-naphthylmethyl) piperazine, (3)(2R)-4-(4-Morpholino-2-butynyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl) piperazine, (4)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(morpholinoamino)propyl]piperazine and (5)(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-morpholino-2-butenyl]piperazine, or a pharmaceuticallyacceptable salt thereof.
 9. A process for the preparation of compound ofthe following general formula:

wherein Y is bond or lower alkylene, R¹ is aryl which may have suitablesubstituent(s), R² is aryl or indolyl each of which may have suitablesubstituent(s), R³ is hydrogen or lower alkyl, R⁴ ischloro(lower)alkenyl; chloro(lower)alkynyl;pyridyl(lower)alkylamino(lower)alkyl;pyridyl(lower)alkylamino(lower)alkenyl; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino (lower)alkyl;triazolylamino(lower)alkyl; lower alkoxy(lower)alkylamino(lower)alkyl;bis[(lower)alkoxy(lower)alkyl]amino(lower)alkyl; N-(loweralkyl)-N-[(lower)alkoxy(lower)alkyl]amino (lower) alkyl;hydroxy(lower)alkyl; lower alkylsulfonyloxy(lower)alkyl;phenyl(lower)alkyl which may have lower alkanoyl, amino, loweralkanoylamino, di(lower)alkylaminocarbonyl or nitro; loweralkoxyphenyl(lower)alkylcarbonyl; lower alkanoylbenzoyl;benzoyl(lower)alkyl which has lower alkyl, chlorine ordi(lower)alkylamino; benzoyl(lower)alkyl which has halogen and loweralkyl; dihalobenzoyl(lower)alkyl; di(lower)alkylbenzoyl(lower)alkyl;3-fluorobenzoyl(lower)alkyl; 3-(4-fluorobenzoyl)propyl;4,4-ethylenedioxy-4-(4-fluorophenyl)butyl;piperazinylcarbonyl(lower)alkyl which has cyclopentyl or halophenyl;(2-pyridyl)(lower)alkyl; (3-pyridyl)propyl; (3-pyridyl)(lower)alkynyl;imidazolyl(lower)alkyl which may have lower alkyl; pyrazolyl(lower)alkylwhich may have lower alkyl; thiomorpholinylcarbonyl(lower)alkyl;(3-azabicyclo[3.2.2]non-3-yl)carbonyl(lower)alkyl; orthienylcarbonyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl,1,2,3,6-tetrahydropyridyl(lower)alkynyl,1,2,3,4-tetrahydroisoquinolyl(lower)alkyl,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl(lower) alkyl, saturatedheterocyclic(lower)alkyl, saturated heterocyclic(lower)alkenyl,saturated heterocyclic(lower)alkynyl, saturatedheterocyclicamino(lower)alkyl, saturated heterocyclicamino(lower)alkenylor saturated heterocyclicamino(lower)alkynyl, each of which may havesuitable substituent(s), or a salt thereof, which comprises (1) reactinga compound of the formula:

 or its reactive derivative at the imino group or a salt thereof with acompound of the formula W₁-R⁴  or a salt thereof to provide a compoundof the formula:

 or a salt thereof, in the above formulas, Y, R¹, R², R³ and R⁴ are eachas defined above, and W₁ is a leaving group, or (2) reacting a compoundof the formula:

 or its reactive derivative at the imino group or a salt thereof with acompound of the formula:

 or its reactive derivative at the carboxy group or a salt thereof toprovide a compound of the formula:

 or a salt thereof, in the above formulas, Y, R¹, R² and R³ are each asdefined above, and R⁵ is lower alkoxyphenyl(lower)alkyl or loweralkanoylphenyl, or (3) reacting a compound of the formula:

 or its reactive derivative at the carboxy group or a salt thereof witha compound of the formula: H-R⁶  or a salt thereof to provide a compoundof the formula:

 or a salt thereof, in the above formulas, Y, R¹, R² and R³ are each asdefined above, X is lower alkylene, and R⁶ is piperazinyl which hascyclopentyl or halophenyl; or thiomorpholinyl, or (4) subjecting acompound of the formula:

 or a salt thereof to an acylation reaction to provide a compound of theformula:

 or a salt thereof, in the above formulas, X, Y, R¹, R² and R³ are eachas defined above, and R⁷ is acyloxy, or (5) reacting a compound of theformula:

 or a salt thereof with a compound of the formula: H-R⁸  or a saltthereof to provide a compound of the formula:

 or a salt thereof, in the above formulas, X, Y, R¹, R² and R³ are eachas defined above, and R⁸ is pyridyl(lower)alkylamino; N-(loweralkyl)-N-[pyridyl(lower)alkyl]amino; triazolylamino; morpholinoamino;lower alkoxy(lower)alkylamino; bis[(lower)alkoxy(lower)alkyl]amino;N-(lower alkyl)-N-[(lower)alkoxy(lower)alkyl]amino; imidazolyl;pyrazolyl; or 1,2,3,6-tetrahydropyridyl, 1,2,3,4-tetrahydroisoquinolyl,4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic, eachof which may have suitable substituent(s), or (6) subjecting a compoundof the formula:

 or a salt thereof to a reduction reaction to provide a compound of theformula:

 or a salt thereof, in the above formulas, X, Y, R¹, R² and R³ are eachas defined above, or (7) reacting a compound of the formula:

 or a salt thereof with a compound of the formula: W₂-R⁹  or a saltthereof to provide a compound of the formula:

 or a salt thereof, in the above formulas, X, Y, R¹, R² and R³ are eachas defined above, W₂ is a leaving group, and R⁹ is lower alkanoyl.
 10. Apharmaceutical composition which comprises, as an active ingredient, acompound of claim 1 or a pharmaceutically acceptable salt thereof inadmixture with pharmaceutically acceptable carriers.
 11. A use of acompound of claim 1 as a medicament.
 12. A method for treating orpreventing Tachykinin-mediated diseases which comprises administering aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof to human being or animals.
 13. A compound ofclaim 1 for use as a medicament.
 14. Use of a compound of claim 1 formanufacture of a medicament for treating or preventingTachykinin-mediated diseases.